Compound for the sequestration of undesirable antibodies in a patient

ABSTRACT

The present invention provides a compound for the sequestration of undesirable antibodies (e.g. related to an autoimmune disease) in a patient. The compound comprises an inert biopolymer scaffold and at least a first peptide n-mer of the general formula P(-S-P) (n-1)  and a second peptide n-mer of the general formula P(-S-P) (n-1) ; wherein, independently for each occurrence, P is a peptide with a sequence length of 2-13 amino acids and S is a non-peptide spacer, wherein, independently for each of the peptide n-mers, n is an integer of at least 1, wherein each of the peptide n-mers is bound to the biopolymer scaffold. Also provided are pharmaceutical compositions comprising the compound, as well as a method of sequestering one or more antibodies present in an individual and a method of inhibiting an immune reaction to a treatment with an active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 17/424,791, filed Jul. 21, 2021 and which is a U.S.National Stage Application of PCT/EP2020/058024 assigned internationalfiling date of Mar. 23, 2020 and claiming foreign priority to EP patentapplication 19164784.1 filed Mar. 23, 2019, the disclosure of all theseapplications is herein incorporated by reference.

INCORPORATION BY REFERENCE OF THE SEQUENCE LISTING

The content of the ASCII text file of the sequence listing named18Z0488.TXT, 6 kb in size, created on Aug. 3, 2021, is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The field of present invention relates to compounds for thesequestration of undesirable antibodies in an individual, such asantibodies related to autoimmune diseases.

BACKGROUND

In general, antibodies are essential components of the humoral immunesystem, offering protection from infections by foreign organismsincluding bacteria, viruses, fungi or parasites. However, under certaincircumstances—including autoimmune diseases, organ transplantation,blood transfusion or upon administration of biomolecular drugs or genedelivery vectors—antibodies can target the patient's own body (or theforeign tissue or cells or the biomolecular drug or vector justadministered), thereby turning into harmful or disease-causing entities.Certain antibodies can also interfere with probes for diagnosticimaging. In the following, such antibodies are generally referred to as“undesired antibodies” or “undesirable antibodies”.

With few exceptions, selective removal of undesired antibodies has notreached clinical practice. It is presently restricted to very fewindications: One of the known techniques for selective antibody removal(although not widely established) is immunoapheresis. In contrast toImmunoapheresis (which removes Immunoglobulin), selectiveimmunoapheresis involves the filtration of plasma through anextracorporeal, selective antibody-adsorber cartridge that will depletethe undesired antibody based on selective binding to its antigen bindingsite. Selective immunoapheresis has for instance been used for removinganti-A or anti-B antibodies from the blood prior to AB0-incompatibletransplantation or with respect to indications in transfusion medicine(Teschner et al). Selective apheresis was also experimentally applied inother indications, such as neuroimmunological indications (Tetala et al)or myasthenia gravis (Lazaridis et al), but is not yet established inthe clinical routine. One reason that selective immunoapheresis is onlyhesitantly applied is the fact that it is a cost intensive andcumbersome intervention procedure that requires specialized medicalcare. Moreover it is not known in the prior art how to deplete undesiredantibodies rapidly and efficiently.

Unrelated to apheresis, Morimoto et al. discloses dextran as a generallyapplicable multivalent scaffold for improving immunoglobulin-bindingaffinities of peptide and peptidomimetic ligands such as the FLAGpeptide. WO 2011/130324 A1 relates to compounds for prevention of cellinjury. EP 3059244 A1 relates to a C-met protein agonist.

As mentioned, apheresis is applied extracorporeally. By contrast, alsoseveral approaches to deplete undesirable antibodies intracorporeallywere proposed in the prior art, mostly in connection with certainautoimmune diseases involving autoantibodies or anti-drug antibodies:

Lorentz et al discloses a technique whereby erythrocytes are charged insitu with a tolerogenic payload driving the deletion of antigen-specificT cells. This is supposed to ultimately lead to reduction of theundesired humoral response against a model antigen. A similar approachis proposed in Pishesha et al. In this approach, erythrocytes are loadedex vivo with a peptide-antigen construct that is covalently bound to thesurface and reinjected into the animal model for general immunotoleranceinduction.

WO 92/13558 A1 relates to conjugates of stable nonimmunogenic polymersand analogs of immunogens that possess the specific B cell bindingability of the immunogen and which, when introduced into individuals,induce humoral anergy to the immunogen. Accordingly, these conjugatesare disclosed to be useful for treating antibody-mediated pathologiesthat are caused by foreign- or self-immunogens. In this connection, seealso EP 0498658 A2.

Taddeo et al discloses selectively depleting antibody producing plasmacells using anti-CD138 antibody derivatives fused to an ovalbumin modelantigen thereby inducing receptor crosslinking and cell suicide in vitroselectively in those cells that express the antibody against the modelantigen.

Apitope International NV (Belgium) is presently developing solubletolerogenic T-cell epitope peptides which may lead to expression of lowlevels of co-stimulatory molecules from antigen presenting cellsinducing tolerance, thereby suppressing antibody response (see e.g.Jansson et al). These products are currently under preclinical and earlyclinical evaluation, e.g. in multiple sclerosis, Grave's disease,intermediate uveitis, and other autoimmune conditions as well as FactorVIII intolerance.

Similarly, Selecta Biosciences, Inc. (USA) is currently pursuingstrategies of tolerance induction by so-called Synthetic VaccineParticles (SVPs). SVP-Rapamycin is supposed to induce tolerance bypreventing undesired antibody production via selectively inducingregulatory T cells (see Mazor et al).

Mingozzi et al discloses decoy adeno-associated virus (AAV) capsids thatadsorb antibodies but cannot enter a target cell.

WO 2015/136027 A1 discloses carbohydrate ligands presenting the minimalHuman Natural Killer-1 (HNK-1) epitope that bind to anti-MAG(myelin-associated glycoprotein) IgM antibodies, and their use indiagnosis as well as for the treatment of anti-MAG neuropathy. WO2017/046172 A1 discloses further carbohydrate ligands and moieties,respectively, mimicking glycoepitopes comprised by glycosphingolipids ofthe nervous system which are bound by anti-glycan antibodies associatedwith neurological diseases. The document further relates to the use ofthese carbohydrate ligands/moieties in diagnosis as well as for thetreatment of neurological diseases associated with anti-glycanantibodies.

US 2004/0258683 A1 discloses methods for treating systemic lupuserythematosus (SLE) including renal SLE and methods of reducing risk ofrenal flare in individuals with SLE, and methods of monitoring suchtreatment. One disclosed method of treating SLE including renal SLE andreducing risk of renal flare in an individual with SLE involves theadministration of an effective amount of an agent for reducing the levelof anti-double-stranded DNA (dsDNA) antibody, such as a dsDNA epitope asin the form of an epitope-presenting carrier or an epitope-presentingvalency platform molecule, to the individual.

U.S. Pat. No. 5,637,454 relates to assays and treatments of autoimmunediseases. Agents used for treatment might include peptides homologous tothe identified antigenic, molecular mimicry sequences. It is disclosedthat these peptides could be delivered to a patient in order to decreasethe amount of circulating antibody with a particular specificity.

US 2007/0026396 A1 relates to peptides directed against antibodies,which cause cold-intolerance, and the use thereof. It is taught that byusing the disclosed peptides, in vivo or ex vivo neutralization ofundesired autoantibodies is possible. A comparable approach is disclosedin WO 1992/014150 A1 or in WO 1998/030586 A2.

WO 2018/102668 A1 discloses a fusion protein for selective degradationof disease-causing or otherwise undesired antibodies. The fusion protein(termed “Seldeg”) includes a targeting component that specifically bindsto a cell surface receptor or other cell surface molecule atnear-neutral pH, and an antigen component fused directly or indirectlyto the targeting component. Also disclosed is a method of depleting atarget antigen-specific antibody from a patient by administering to thepatient a Seldeg having an antigen component configured to specificallybind the target antigen-specific antibody.

WO 2015/181393 A1 concerns peptides grafted intosunflower-trypsin-inhibitor-(SFTI-) and cyclotide-based scaffolds. Thesepeptides are disclosed to be effective in autoimmune disease, forinstance citrullinated fibrinogen sequences that are grafted into theSFTI scaffold have been shown to block autoantibodies in rheumatoidarthritis and inhibit inflammation and pain. These scaffolds aredisclosed to be non-immunogenic.

Erlandsson et al discloses in vivo clearing of idiotypic antibodies withanti-idiotypic antibodies and their derivatives.

Berlin Cures Holding AG (Germany) has proposed an intravenous broadspectrum neutralizer DNA aptamer (see e.g. WO 2016/020377 A1 and WO2012/000889 A1) for the treatment of dilated cardiomyopathy and otherGPCR-autoantibody related diseases that in high dosage is supposed toblock autoantibodies by competitive binding to the antigen bindingregions of autoantibodies. In general, aptamers did not yet achieve abreakthrough and are still in a preliminary stage of clinicaldevelopment. The major concerns are still biostability andbioavailability, constraints such as nuclease sensitivity, toxicity,small size and renal clearance. A particular problem with respect totheir use as selective antibody antagonists are their propensity tostimulate the innate immune response.

WO 00/33887 A2 discloses methods for reducing circulating levels ofantibodies, particularly disease-associated antibodies. The methodsentail administering effective amounts of epitope-presenting carriers toan individual. In addition, ex vivo methods for reducing circulatinglevels of antibodies are disclosed which employ epitope-presentingcarriers.

U.S. Pat. No. 6,022,544 A relates to a method for reducing an undesiredantibody response in a mammal by administering to the mammal anon-immunogenic construct which is free of high molecular weightimmunostimulatory molecules. The construct is disclosed to contain atleast two copies of a B cell membrane immunoglobulin receptor epitopebound to a pharmaceutically acceptable non-immunogenic carrier.

However, the approaches to deplete undesirable antibodiesintracorporeally disclosed in the prior art have many shortcomings. Inparticular, neither of them has been approved for regular clinical use.

SUMMARY

It is thus an object of the present invention to provide improvedcompounds and methods for intracorporeal depletion (or sequestration) ofundesired antibodies (such as antibodies related to autoimmune disease)in an individual, in particular for use in treatment or prevention of adisease or condition related to the undesired antibody (e.g. ofautoimmune disease).

The present invention provides a compound comprising

-   -   a biopolymer scaffold and at least    -   a first peptide n-mer of the general formula:

P(-S-P)_((n-1)) and

-   -   a second peptide n-mer of the general formula:

P(-S-P)_((n-1)).

Independently for each occurrence, P is a peptide with a sequence lengthof 2-13 amino acids, preferably 3-11 amino acids, more preferably 4-9amino acids, especially 5-8 amino acids, and S is a non-peptide spacer.Independently for each of the peptide n-mers, n is an integer of atleast 1, preferably of at least 2, more preferably of at least 3, evenmore preferably of at least 4, especially of at least 5. Each of thepeptide n-mers is bound to the biopolymer scaffold, preferably via alinker each.

Preferably, at least one occurrence of P is P_(a) and/or at least oneoccurrence of P is P_(b). P_(a) is a defined peptide (i.e. a peptide ofdefined sequence) with a sequence length of 2-13 amino acids, preferably3-11 amino acids, more preferably 4-9 amino acids, especially 5-8 aminoacids. P_(b) is a defined peptide (i.e. a peptide of defined sequence)with a sequence length of 2-13 amino acids, preferably 3-11 amino acids,more preferably 4-9 amino acids, especially 5-8 amino acids.

The present invention also provides a compound comprising

-   -   a biopolymer scaffold and at least    -   a first peptide n-mer which is a peptide dimer of the formula        P_(a)-S-P_(a) or P_(a)-S-P_(b), wherein P_(a) is a defined        peptide (i.e. a peptide of defined sequence) with a sequence        length of 2-13 amino acids, preferably 3-11 amino acids, more        preferably 4-9 amino acids, especially 5-8 amino acids, P_(b) is        a defined peptide (i.e. a peptide of defined sequence) with a        sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer, wherein the first peptide        n-mer is bound to the biopolymer scaffold, preferably via a        linker.

This compound preferably comprises a second peptide n-mer which is apeptide dimer of the formula P_(b)-S-P_(b) or P_(a)-S-P_(b), wherein thesecond peptide n-mer is bound to the biopolymer scaffold, preferably viaa linker.

The present invention further provides a compound, preferably for thesequestration (or depletion) of anti human muscle nicotinicacetylcholine receptor (AChR) antibodies, anti human muscle-specificreceptor tyrosine kinase antibodies and/or anti human low-densitylipoprotein receptor related protein 4 antibodies present in a humanindividual, the compound comprising a biopolymer scaffold and at leasttwo peptides with a sequence length of 7-13 amino acids, wherein each ofthe peptides independently comprises a 7-13 amino-acid sequence fragmentof the AChR subunit alpha sequence identified by UniProt accession codeP02708 (optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)) or of the muscle-specificreceptor tyrosine kinase sequence identified by UniProt accession code015146 or of the low-density lipoprotein receptor related protein 4sequence identified by UniProt accession code 075096 (optionally whereinthe sequence fragment comprises at most five, preferably at most four,more preferably at most three, even more preferably at most two,especially at most one amino acid substitutions (e.g. such that amimotope is formed)), wherein the peptides are covalently bound to thebiopolymer scaffold, preferably via a linker, wherein the biopolymerscaffold is selected from the group consisting of human globulins andhuman albumin.

The present invention also provides a compound, preferably for thesequestration (or depletion) of anti-Epstein-Barr virus nuclear antigen1 (EBNA-1) antibodies, anti human melatonin-related receptor (GPR50)antibodies and/or anti human type-1 angiotensin II receptor (AT1AR)antibodies present in a human individual, the compound comprising abiopolymer scaffold and at least two peptides with a sequence length of7-13 amino acids, wherein each of the peptides independently comprises a7-13 amino-acid sequence fragment of the EBNA1 sequence identified byUniProt accession code Q1HVF7 or P03211 or of the GPR50 sequenceidentified by UniProt accession code Q13585 or of the type-1 angiotensinII receptor (AT1AR) sequence identified by UniProt accession codeP30556, wherein the peptides are covalently bound to the biopolymerscaffold, preferably via a linker, wherein the biopolymer scaffold isselected from the group consisting of human globulins, preferably fromthe group consisting of human immunoglobulins and human haptoglobin, andhuman albumin.

Furthermore, the present invention provides a pharmaceutical compositioncomprising any one of the aforementioned compounds and at least onepharmaceutically acceptable excipient. Preferably, this pharmaceuticalcomposition is for use in therapy, in particular of any one of thediseases or conditions mentioned herein.

In another aspect, the present invention provides a method ofsequestering (or depleting) one or more antibodies present in anindividual, comprising obtaining a pharmaceutical composition as definedherein, the composition being non-immunogenic in the individual, wherethe one or more antibodies present in the individual are specific for atleast one occurrence of P, or for peptide P_(a) and/or peptide P_(b);and administering the pharmaceutical composition to the individual.

In yet another aspect, the present invention relates to a pharmaceuticalcomposition, comprising the compound defined herein and furthercomprising an active agent and optionally at least one pharmaceuticallyacceptable excipient. The active agent comprises a peptide fragment witha sequence length of 2-13 amino acids, preferably 3-11 amino acids, morepreferably 4-9 amino acids, especially 5-8 amino acids. The sequence ofat least one occurrence of peptide P, or peptide P_(a) and/or peptideP_(b), of the compound is at least 70% identical, preferably at least75% identical, more preferably at least 80% identical, yet morepreferably at least 85% identical, even more preferably at least 90%identical, yet even more preferably at least 95% identical, especiallycompletely identical to the sequence of said peptide fragment.Preferably, this pharmaceutical composition is for use in prevention orinhibition of an immune reaction against the active agent.

In even yet another aspect, the present invention provides a method ofinhibiting an immune reaction to a treatment with an active agent in anindividual in need of treatment with the active agent, comprisingobtaining said pharmaceutical composition comprising the compound andthe active agent; wherein the compound of the pharmaceutical compositionis non-immunogenic in the individual, and administering thepharmaceutical composition to the individual.

In a further aspect, the present invention provides a method ofproviding the compound of the invention, comprising the steps ofidentifying at least one individual having an undesired antibody againstan antigen, screening a peptide library to identify a peptide mimotopefor which the undesired antibody is specific, and providing thecompound, wherein at least one occurrence of P of the compound comprisesthe entire sequence of the peptide mimotope.

In the course of the present invention, it was surprisingly found thatthe compound of the present invention is particularly effective inreducing titres of undesired antibodies in an individual. In particular,the compound achieved especially good results with regard toselectivity, duration of titre reduction and/or level of titre reductionin an in vivo model (see experimental examples).

DETAILED DESCRIPTION

The detailed description given below relates to all of the above aspectsof the invention unless explicitly excluded.

Intracorporeal depletion of undesired antibodies (as achieved by thepresent invention) is for example advantageous in autoimmune diseases,organ- and cell transplantation, blood transfusion, or with respect toantibodies that are directed against biotherapeutics, substitutiontherapeutics or viral gene delivery vectors (such as AAV) or even indiagnostic imaging or in emergency intervention following antibodytreatment or active vaccination. In particular, with respect toautoimmune diseases, several hundreds of autoimmune conditions areconnected to autoantibodies that bind to defined self-epitopes orneoepitopes present in the body. There appears to be practically norestriction with respect to organs or tissues that can be affected bydisease-causing autoantibodies: Table 1 below lists some examples toillustrate the diversity of indication fields where it is beneficial totarget undesired antibodies selectively.

TABLE 1 Exemplary list of applications of the present invention:AUTOIMMUNE ANTI-DRUG and NEUTRALIZING DISEASES ANTIBODIES CNS & MuscleADAs/nABs against coagulation factors MOG seropositive ADAs/nABs againstenzymes neuromyelitis ADAs/nABs against growth optica spectrum disordersfactors and hormones Neuromyelitis Optica ADAs/nABs against fusionproteins Autoimmune-Encephalitis and decoy receptor drugs MultipleSclerosis TRANSPLANTATION and Amyotrophic Lateral Sclerosis TRANSFUSIONMEDICINE SLE dementia Alloantibodies Myasthenia gravis Blood groupantibodies Heart & Organs: AB0-incompatible Dilatative Cardiomyopathy,organ Transplantation pulmonary hypertension EMERGENCY INTERVENTIONChagas’ Disease Active vaccine intervention other diseases with(therapeutic vaccines) β1-adrenergic receptors Passive vaccineintervention Primary biliary cholangitis (therapeutic mABs) Sjögren’sSyndrome Cytokine Release Syndrome Caeliac Disease (e.g. After CARTtreatment) Graves Disease VIRAL VECTORS Goodpasture Disease IN GENETHERAPY Systemic conditions: IN VIVO Systemic Lupus DIAGNOSTIC IMAGINGErythematosus Sjögren’s syndrome Systemic Sclerosis Behcet’s DiseaseHypertension type I Diabetes type II Diabetes Preeclampsia Blood: ImmuneThrombocytopenic Purpura (ITP) Skin: pemphigus vulgaris bullouspemphigoid Epidermolysis bullosa acquista and bullous SLE

For instance, in transplantation medicine, undesired alloantibodies mayoccur. Alloantibodies are antibodies directed against foreign tissueantigens which can contribute to accelerated transplant rejection aftertransplantation (Garces et al, 2017). Upon tissue-, bone marrow- andstem cell transplantation, foreign tissue antigens are recognized byT-cells and B-cells producing antibodies against major and minorhistocompatibility antigens. Inverse correlation between transplantsurvival and alloantibody levels confirms the pathogenic role ofalloantibodies. Further, depletion of undesired blood group antibodiesbefore and after AB0-incompatible transplantation of organs have beenshown to be beneficial to transplant survival (Rummler et al, 2016).

Anti-drug Antibodies (ADAs), sometimes also referred to as neutralizingantibodies (nABs), are a category of undesired antibodies having emergedwith the advent of biological drugs carrying epitopes that arerecognized as “foreign” thereby inducing an anti-drug antibody response.This immune response can induce neutralizing antibodies (e.g. acting bydepletion or blocking of the drug, or by forming immunocomplexes), aphenomenon that correlates with the amount of “foreign” sequences of thedrug, inherent immunogenicity of the drug and, importantly, with thepropensity to aggregate and to form complexes, once the drug is in theplasma (Moussa et al, 2016). Examples of drugs inducing ADAs includecertain antibodies such as anti TNF-alpha antibodies, substitutiontherapeutics such as Hemophilia Factor VIII or enzymes used in enzymereplacement therapies such as Fabry Disease or such as uricase for thetreatment of refractory gout and other classes of biologicaltherapeutics such as e.g. erythropoietin or interferon.

Similar to the situation with ADAs, pre-existing or induced undesiredantibodies against gene therapy vectors are an emerging problem in thefield of gene therapy (see e.g. Mingozzi & High, 2017): Gene therapy israpidly progressing and Adeno Associated Viruses (AAV) but also otherviral vector gene delivery vectors show promising preclinical andclinical results. This is particularly important for hematologicdiseases such as hemophilia, or in Gaucher disease, porphyria orhemochromatosis or several other genetic diseases with enzyme defects.Much effort has been invested into optimization of AAV vectors, howeverthe problem of pre-existing antibodies or newly induced antibodiesagainst the vector, but also their T-cell immunogenicity is not yetsolved. Several strategies to overcome B-cell and T-cell immunity wereproposed including serological pre-selection of the target patientseligible for AAV treatment, high vector dosing, capsid decoys thatpre-adsorb or deplete pre-existing or newly induced anti AAV antibodies,co-administration of decoy T-cell receptors or less selective approachessuch as concomitant immunosuppression. The more pragmatic approacheswere AAV serotype switching, plasma exchange therapies, selectiveimmunoapheresis or local application of AAV vectors. Essentially, theimmunological strategies boiled down to immunosuppression or toleranceinduction. However, none of these strategies could solve the problem ofpre-existing neutralizing anti AAV antibodies satisfactorily (see e.g.Majowicz et al.). The main disadvantage of the capsid decoy strategy wasthat empty capsids were processed by target cells similar to intact AAVparticles, thereby facilitating antigen presentation by MHC I andstimulation of T-cells ultimately providing an immunostimulatory effect.

More than 2000 clinical trials for gene therapy (mostly clinical phase Ior II trials) were undertaken during the last years. Monogeneticdiseases still constitute a significant portion of the typicalindications for gene-based therapies. They include a great diversity ofindication fields, such as primary immunodeficiencies, inheritedneurological disorders, cystic fibrosis, ocular disorders,hemoglobinopathies, hemophilias, alpha-1-antitrypsin deficiencies,lipoprotein lipase deficiency, enzyme defects, and many others. Otherformats of gene therapy-based strategies such as Chimeric AntigenReceptor T-Cells (CAR T-Cells) evolve rapidly but still carry the riskfor humoral responses against functional components of the system, suchas switches, suicide gene products or other non-self and modifiedprotein components, or against the viral gene delivery components orneo-antigens emerging by uncontrolled gene insertions into proteincoding sequences. Mechanistically, gene therapy includes gene repairstrategies, genome editing technologies and stable or transient geneexpression strategies. As mentioned above, a common challenge remainsthat patients carry pre-existing neutralizing antibodies against viralgene therapy vectors that reduce the efficacy. Importantly, viral genetherapy vectors are often capable of inducing T-cell responses andneutralizing antibodies against viral proteins and their products. Inaddition, antibody- or T-cell responses can be introduced against thegene product itself or against the introduced DNA editing machinery suchas components of the CRISPR/Cas9 containing natural or artificiallymodified endonucleases (such as prototype Cas9) that can be applied fortherapeutic genome editing. Therefore, neutralizing antibodies thataffect gene therapy efficacy remain a major challenge in the field ofviral gene therapy vector development, in particular when using AAVs,lentiviruses or retroviruses.

Finally, in the context of safety intervention in active immunizationtrials (i.e. therapeutic vaccination) or passive treatments withantibodies or antibody-like compounds, interventional drugs for rapidselective antibody removal of e.g. therapeutic antibodies orantibody-like biotherapeutic compounds that cause complications underemergency conditions are needed. For these situations, there isespecially a lack of rapid and effective selective antibody loweringstrategies.

In response to the lack of satisfactory therapeutic strategies that canrapidly and safely remove undesired antibodies such as e.g. myastheniagravis during a myasthenic crisis, before administration of asubstitution therapeutic, before applying a gene targeting vector or incase of an adverse event induced by a therapeutic antibody or anyantibody-like biological compound, the present invention provides aparticularly suitable solution. The present invention represents aplatform for flexible, optionally personalized, biotherapeutics that canbe adapted to any type of undesired or harmful polyclonal or monoclonalantibody. In particular, these biotherapeutics can remove undesiredantibodies rapidly, making them suitable for urgent interventions.

The biopolymer scaffold used in the present invention may be a mammalianbiopolymer such as a human biopolymer, a non-human primate biopolymer, asheep biopolymer, a pig biopolymer, a dog biopolymer or a rodentbiopolymer. In particular the biopolymer scaffold is a protein,especially a (non-modified or non-modified with respect to itsamino-acid sequence) plasma protein. Preferably, the biopolymer scaffoldis a mammalian protein such as a human protein, a non-human primateprotein, a sheep protein, a pig protein, a dog protein or a rodentprotein. Typically, the biopolymer scaffold is a non-immunogenic and/ornon-toxic protein that preferably circulates in the plasma of healthy(human) individuals and can e.g. be efficiently scavenged or recycled byscavenging receptors, such as e.g. present on myeloid cells or on liversinusoidal endothelial cells (reviewed by Sorensen et al 2015).

According to a particular preference, the biopolymer scaffold is a(preferably human) globulin, preferably selected from the groupconsisting of immunoglobulins, alpha1-globulins, alpha2-globulins andbeta-globulins, in particular immunoglobulin G, haptoglobin andtransferrin. Haptoglobin in particular has several advantageousproperties, as shown in Examples 5-9, especially an advantageous safetyprofile.

The biopolymer scaffold may also be (preferably human) albumin,hemopexin, alpha-1-antitrypsin, C1 esterase inhibitor, lactoferrin ornon-immunogenic (i.e. non-immunogenic in the individual to be treated)fragments of all of the aforementioned proteins, including theglobulins.

The peptides (or peptide n-mers) are preferably covalently conjugated(or covalently bound) to the biopolymer scaffold via a (non-immunogenic)linker known in the art such as for example amine-to-sulfhydryl linkersand bifunctional NHS-PEG-maleimide linkers or other linkers known in theart. Alternatively, the peptides (or peptide n-mers) can be bound to theepitope carrier scaffold e.g. by formation of a disulfide bond betweenthe protein and the peptide (which is also referred to as “linker”herein), or using non-covalent assembly techniques, spontaneousisopeptide bond formation or unnatural amino acids for bio-orthogonalchemistry via genetic code expansion techniques (reviewed by Howarth etal 2018 and Lim et al 2016).

The compound of the present invention may comprise e.g. at least two,preferably between 3 and 40 copies of one or several different peptides(which may be present in different forms of peptide n-mers as disclosedherein). The compound may comprise one type of epitopic peptide (inother words: antibody-binding peptide or paratope-binding peptide),however the diversity of epitopic peptides bound to one biopolymerscaffold molecule can be a mixture of e.g. up to 8 different epitopicpeptides.

Typically, since the peptides present in the inventive compoundspecifically bind to selected undesired antibodies, their sequence isusually selected and optimized such that they provide specific bindingin order to guarantee selectivity of undesired antibody depletion fromthe blood. For this purpose, the peptide sequence of the peptidestypically corresponds to the entire epitope sequence or portions of theundesired antibody epitope. The peptides used in the present inventioncan be further optimized by exchanging one, two or up to four amino-acidpositions, allowing e.g. for modulating the binding affinity to theundesired antibody that needs to be depleted. Such single or multipleamino-acid substitution strategies that can provide “mimotopes” withincreased binding affinity and are known in the field and werepreviously developed using phage display strategies or peptidemicroarrays (see e.g. Application Note, “T PEPperMAP® Full SubstitutionScan of HA and M13 Epitopes”, by PEPperPRINT GmbH, Heidelberg, Germany).In other words, the peptides used in the present invention do not haveto be completely identical to the native epitope sequences of theundesired antibodies.

Typically, the peptides used in the compound of the present invention(e.g. peptide P or P_(a) or P_(b) or P₁ or P₂) are composed of one ormore of the 20 amino acids commonly present in mammalian proteins. Inaddition, the amino acid repertoire used in the peptides may be expandedto post-translationally modified amino acids e.g. affecting antigenicityof proteins such as post translational modifications, in particularoxidative post translational modifications (see e.g. Ryan 2014) ormodifications to the peptide backbone (see e.g. Müller 2018), or tonon-natural amino acids (see e.g. Meister et al 2018). Thesemodifications may also be used in the peptides e.g. to adapt the bindinginteraction and specificity between the peptide and the variable regionof an undesired antibody. In particular, epitopes (and therefore thepeptides used in the compound of the present invention) can also containcitrulline as for example in autoimmune diseases. Furthermore, byintroducing modifications into the peptide sequence the propensity ofbinding to an HLA molecule may be reduced, the stability and thephysicochemical characteristics may be improved or the affinity to theundesired antibody may be increased.

In many cases, the undesired antibody that is to be depleted is oligo-or polyclonal (e.g. autoantibodies, ADAs or alloantibodies are typicallypoly- or oligoclonal), implying that undesired (polyclonal) antibodyepitope covers a larger epitopic region of a target molecule. To adaptto this situation, the compound of the present invention may comprise amixture of two or several epitopic peptides (in other words:antibody-binding peptides or paratope-binding peptides), therebyallowing to adapt to the polyclonality or oligoclonality of an undesiredantibody.

Such poly-epitopic compounds of the present invention can effectivelydeplete undesired antibodies and are more often effective thanmono-epitopic compounds in case the epitope of the undesired antibodyextends to larger amino acid sequence stretches.

It is advantageous if the peptides used for the inventive compound aredesigned such that they will be specifically recognized by the variableregion of the undesired antibodies to be depleted. The sequences ofpeptides used in the present invention may e.g. be selected by applyingfine epitope mapping techniques (i.e. epitope walks, peptide deletionmapping, amino acid substitution scanning using peptide arrays such asdescribed in Carter et al 2004, and Hansen et al 2013) on the undesiredantibodies.

Preferably, the peptide used for the inventive compound (e.g. peptide Por P_(a) or P_(b)) comprises an epitope or epitope part (e.g. at leasttwo, preferably at least three, more preferably at least four, even morepreferably at least five, yet even more preferably at least six,especially at least seven or even at least eight amino acids) of one ofthe following antigens (involved in autoimmune diseases) identified bytheir UniProt accession code:

P01023, A8K2U0, P49588, Q5JTZ9, O95477, Q8IZY2, P08183, P33527, O15438,Q961U4, P00519, P42684, Q9BYF1, P22303, Q99798, P68133, P60709, P63261,P12814, O43707, P61158, Q13705, P37023, O75077, Q9UKQ2, Q76LX8, Q6ZMM2,P35611, P07327, P00325, P35348, P25100, P08588, P07550, P25098, P35626,P30566, P43652, P02771, Q5U5Z8, Q15109, P35573, Q9UL18, Q9UKV8, O00468,P01019, P30556, Q09666, P02765, O43918, Q9Y6K8, Q02952, P14550, P15121,O95154, P02768, P00352, P49189, Q9UM73, P09923, P05187, P03971, P49418,P03950, Q9BY76, Q15327, P15144, P04083, P50995, P07355, Q3ZCQ2, P12429,P09525, P08758, P08133, O76027, Q13367, P27695, Q9BZZ5, P02647, P04114,P02749, P05067, P29972, P55087, Q8N726, P05089, Q9UNA1, P52566, Q99819,Q15052, P07306, P04424, P08243, Q9BXN1, P15336, P13637, P05026, P98194,P20648, P51164, P06576, P48047, P54252, Q8WXX7, P01185, P25311, Q9H6S1,P61769, Q13072, O75531, Q99728, P10415, P41182, P11274, O14503, Q93088,O00499, O15392, P35226, P12643, P18075, Q8N8U9, Q13873, P17213, Q9NP55,Q96DR5, Q8TDL5, P15056, Q7Z569, P38398, P51587, Q58F21, Q8IWQ3, Q8NE79,Q9Y224, Q13901, P02745, P01024, P00915, P00918, P07451, O00555, Q00975,Q9NY47, Q9Y698, Q8TC20, Q05682, P27482, P27797, P27824, P04632, P52907,P42574, Q14790, P31415, P41180, P20810, O15446, P04040, Q9NTU7, Q5M9NO,Q3V6T2, P10147, P13501, P20248, P14635, P24385, Q8ND76, P51681, P49368,P48643, P50990, Q9NZQ7, P28906, P16671, P04234, P15529, P08174, P13987,P01732, P21926, P30305, P12830, P55291, P22223, P55283, P06493, P42771,P51861, Q01850, Q9H211, P13688, P06731, Q9UNI1, P49450, P07199, Q03188,Q02224, P49454, Q9H3R5, Q92674, Q6IPU0, Q7L2Z9, A8MT69, Q5JTW2, P00751,P08603, Q03591, P36980, Q02985, Q9P2M7, O95992, Q14839, P10645, P36222,Q15782, Q9UKJ5, Q9Y259, P11229, P08172, P20309, P08173, P08912, P02708,Q9UGM1, P11230, Q8NCH0, Q99828, O75339, Q14011, Q07065, P12277, Q96MX0,P06732, A8K714, O95832, O75508, P30622, Q96KN2, Q12860, Q02246, Q8IWV2,O94779, Q9UQ52, P78357, Q9UHC6, Q7Z7A1, P38432, Q5TAT6, Q9UMD9, P02452,Q01955, P29400, Q14031, P12111, Q02388, Q9Y215, P49747, Q14019, P00450,P16870, Q8TCG5, P17927, Q9NS37, Q9UJA2, P02741, P02511, P53674, O95825,O75390, Q9Y600, P04141, P09919, P0DML2, Q14406, Q6UVK1, Q01459, Q9GZU7,P16410, P35222, P53634, P07339, P08311, Q14247, O60494, Q14999, Q86UP6,P61073, P05108, P05093, P04798, P05177, P08686, P11509, P20813, P33261,P11712, P10635, P05181, P08684, Q8N907, P09172, P43146, P07585, P20711,Q16832, Q9NR30, O00571, Q86XP3, Q9NY93, O75398, P35659, P17661, Q96SL1,O94907, P10515, P09622, P36957, P24855, Q8NFT8, O00429, Q8N608, P27487,P42658, Q14195, Q9BPU6, P21728, P14416, Q08554, Q02487, Q14574, Q02413,Q14126, P32926, Q86SJ6, P15924, Q03001, Q9NRD8, Q05923, O75923, O95905,Q9NTX5, Q16610, O43854, P25101, Q15075, P68104, O00418, O95967, P01133,P00533, P20042, P38919, Q04637, P08246, Q12926, Q14576, P26378, P15502,P19622, P06733, P09104, P22413, O43768, P11171, P16422, P07099, P34913,P01588, P11678, P58107, P04626, Q96RT1, Q8IUD2, Q14264, P10768, P03372,Q9Y603, Q92817, Q9Y3B2, Q01780, Q13868, Q9NQT5, Q9NPD3, Q9NQT4, Q5RKV6,Q15024, Q96B26, Q06265, P15311, P00488, P08709, P00451, P00740, P15090,Q14320, P48023, P49327, Q8TES7, P22087, P35555, Q75N90, P09467, P12319,O75015, O75636, Q7L513, P02675, P11362, P62942, Q9UIM3, P20930, Q14315,O75955, Q14254, O43155, P35916, P02751, Q04609, P01225, Q12841, O95954,P02794, P02792, P09958, P35637, P51114, Q9UM11, P35575, O95166, P60520,Q9UBS5, O75899, Q99259, Q05329, Q13065, P22466, Q14376, P04406, P41250,P01350, P15976, P50440, P02774, P01275, Q8N6F7, P23434, P55107, P50395,P56159, Q9UJY5, P01241, P01286, Q9UBU3, P09681, O14908, P29033, Q9NS71,Q6ZMI3, P23415, P15104, Q61B77, P49915, Q13823, P01148, P30968, Q92805,Q08379, Q08378, Q13439, A6NI86, A8MQT2, Q14789, P07359, P55259, P40197,Q9HCN6, P14770, Q9NQX3, P06744, Q13098, P24298, P18283, P42261, P42262,P42263, P48058, O43424, P39086, Q13002, Q16478, Q05586, Q12879, Q13224,Q4V328, Q13255, P41594, P28799, P07492, P08263, P21266, P78417, P09211,Q00403, P35269, P25092, P08236, P02724, P07305, P16104, O75367, P84243,P12081, Q96D42, P68871, Q13547, Q92769, O15379, P56524, Q9UQL6, P19113,Q9UBI9, P51858, Q00341, Q9NRV9, O00291, O75146, P54198, P16402, P58876,P62805, P19367, P09429, P26583, P04035, Q01581, P54868, P05114, P05204,Q14541, P09651, P22626, Q99729, Q14103, P52597, P31943, P31942, P61978,P14866, Q8WVV9, Q9NSC5, Q99714, Q7Z5P4, P14060, P08238, P14625, P0DMV8,P0DMV9, P34932, P11021, P11142, P04792, Q12988, P10809, Q92598, P08908,Q13639, Q9Y4L1, P10997, Q05084, Q9UMF0, 075874, Q5TF58, Q16666, Q9BYX4,P01563, P01574, P01579, Q9NWB7, P05019, P08069, P01344, Q9NZI8, Q9Y6M1,O00425, P11717, P18065, P17936, P01876, P01877, P01854, P01857, P01859,P01860, P01861, A6NGN9, Q8N6C5, P22301, Q13651, Q08334, Q14005, Q16552,Q96PD4, Q14116, P01583, P01584, P14778, P60568, Q9GZX6, P08700, P05112,P05231, P40189, Q96LU5, Q9NV31, P29218, O14732, P12268, Q9NQS7, P01308,Q96T92, P06213, P46940, Q14653, Q13568, P35568, P17301, P08514, P23229,P20701, P11215, P05107, P05106, P16144, Q14643, Q9Y6Y0, 060674, P17275,Q15046, P16389, P22459, Q9UK17, Q9NZI2, Q9NS61, P78508, P48050, P51787,O43525, Q8N513, Q6PI47, P35968, Q9Y4F3, Q96Q89, P43626, P43628, Q5JT82,Q53G59, Q8IXQ5, Q9UKR3, P03952, P26715, P26717, Q13241, P13645, P02533,P19012, P08779, Q04695, P05783, P08727, P12035, Q8N1N4, P05787, Q9NSB2,O15230, P11047, P13473, Q14739, P31025, P13796, P07195, P01130, Q9Y2U8,P09382, P05162, P17931, Q08380, Q3ZCW2, O95970, Q5TDP6, P22888, P49917,P07098, P02545, P20700, Q03252, P61968, P29536, P08519, Q07954, P98164,O75096, Q8TF66, Q32MZ4, Q8ND56, Q9Y4ZO, P02788, Q17RY6, P20645, Q8NHW3,P20916, P43358, O15479, O60732, Q9H0U3, P46821, P11137, Q16584, O43318,P45984, Q16644, P21941, O00339, P56270, P02144, Q9UIS9, P11226, P02686,Q01726, P32245, Q8IVS2, Q99705, Q969V1, Q8TDD5, Q8NE86, P40925, Q00987,O00255, P50579, P46013, Q16655, P03956, P45452, P08253, P09237, P14780,Q13201, Q13875, Q16653, Q13724, Q14149, Q9UBU8, O00566, Q99547, P40238,P05164, Q00013, Q9NZW5, P25189, P22897, Q9Y605, P82909, P43246, P52701,Q13421, P26038, Q9UJ68, P26927, Q13043, Q04912, Q9NZJ7, Q86UE4, P15941,Q8WX17, O15146, Q9UIF7, P10242, P01106, Q99417, P12524, Q8N699, P12882,P35580, P35749, Q9UKX3, Q7Z406, Q9Y2K3, Q9UKX2, P11055, Q9Y623, P13533,P12883, A7E2Y1, P13535, P35579, B0I1T2, P54296, Q14CX7, E9PAV3, Q13765,Q8WY41, Q96159, Q9UBB6, Q9UHB4, Q00604, P28331, P20929, P07196, P07197,Q8NG66, Q8TD19, O60524, O94856, P01138, Q8N4C6, P30414, P59047, Q8N427,Q13253, Q15155, P29475, P51513, Q9UNW9, P55786, O60500, P06748, P01160,P17342, P01303, Q9Y5X4, Q8IXM6, Q9ULB1, Q9HDB5, Q9Y4CO, Q9NXX6, P04629,Q16620, Q16288, Q02818, P80303, Q14980, P49790, Q8TEM1, O15504, Q14990,Q5BJF6, Q9ULJ1, Q6UX06, P78380, P41143, P35372, Q9P0S3, Q92791, Q9UQ80,Q13310, Q9UM07, Q7Z2X7, Q5JRK9, Q96GU1, Q13177, Q99497, P09874, P40424,Q15154, P12004, P29120, Q8WUM4, O95263, O76083, P16234, P09619, O00330,P30101, Q8N165, O00151, Q5T2W1, P16284, P02776, P10720, P35080, P18669,P00558, O95394, P35232, Q99623, Q9BVI0, Q92576, O43175, P11309, O75364,Q9Y446, P04054, Q13018, P16885, Q15149, Q9H7P9, P40967, P29590, Q01453,Q9NR77, P54277, P16233, P54317, Q8ND90, Q9UL42, P00491, Q9H9Y6, O14802,Q99575, P16435, Q15063, Q01851, Q12837, Q15181, P62937, O60437, P35813,P01298, Q9HAZ2, P32119, Q13162, P30041, P13727, Q92954, P17612, P17252,P01236, P04553, P04554, O60678, P04070, Q9UNN8, P54821, Q99811, P07477,P24158, Q9BXM0, O43653, O75475, P20618, P40306, P49721, P28074, P28062,P28065, P61289, Q6PGN9, P26599, Q8WV60, P01270, P06454, Q06124, Q9Y2R2,P08575, Q12913, Q16849, Q92932, Q86Y79, Q9UHX1, P20472, Q9BRP8, P51153,Q9UI14, Q15276, P63244, Q92878, Q06609, P04049, Q15311, Q9UKM9, Q14498,P38159, P10745, Q06330, P53805, O95199, Q9P258, P35243, P46063, P05451,Q8IX06, P57771, P08100, P12271, O60930, O00584, Q9ULK6, Q99942, Q9UBF6,P13489, O75116, Q01973, P15927, Q9Y2JO, Q9UNE2, Q02878, P05388, P05386,P05387, Q9BUL9, P78346, P78345, P62277, P60866, O75676, O43159, Q15404,O00442, Q92541, Q9NQC3, Q9Y265, Q9Y230, P48443, P21817, Q92736, P31151,P04271, P0DJI8, P0DJI9, P10523, P49591, O43290, Q99590, Q8WTV0, Q14108,P13521, P05408, Q14524, Q9BWW7, P34741, Q86SQ7, Q9UDX4, Q13228, P16109,P04279, Q9HC62, P49908, Q9HD40, P01009, P05543, P30740, P29508, P48594,P35237, P05121, P07093, P05155, Q9BYW2, Q7Z333, Q8N474, Q9BWM7, Q99961,O15266, O60902, Q9NYZ4, Q9Y336, Q9H0K1, Q14190, Q13239, Q14493, Q9H0C2,P12235, P05141, Q9H2B4, O43511, P11168, Q8IWU4, O00400, P08195, Q8IWA5,P48751, Q9Y6R1, Q9BRV3, Q92911, P37840, O76070, P08621, P09012, P14678,P09234, P62314, P62316, P62318, P62304, P62306, P62308, P63162, O14512,P00441, P04179, Q9BQB4, O00570, P56693, P35716, O15370, O60248, Q9UN79,O95416, Q9H6I2, P35713, P48431, Q9Y651, P41225, O94993, Q06945, P35711,P35712, Q9BT81, P57073, P48436, P08047, P23497, Q13342, Q9H930, Q15506,Q8N0X2, P00995, P16150, O43791, P10451, Q8TCT8, Q8TCT7, Q8TCT6, Q13813,Q13501, P10124, P61011, O76094, Q05066, P05455, O43805, P61278, Q13586,Q9P246, P31948, P49842, P16949, Q7Z7C7, Q13033, O75558, P61266, Q13190,Q8IWZ8, Q9Y2ZO, Q8IWU6, P63165, P61956, P17600, P08247, P21579, P37837,Q15633, Q13148, P26639, Q9NYW0, P20226, O60806, P24557, P17987, O60522,O14746, P02787, P05549, Q92734, P10646, P02786, P01266, P01137, P21980,Q08188, P49221, P07204, P40225, P10827, P10828, Q9UPZ6, P31483, P29401,Q9Y490, O60602, Q8TDI7, P17152, P42167, P42166, P01375, O00300, P43489,P19237, P48788, P19429, P13805, P45379, P45378, P09430, Q8NDV7, P11387,Q969P6, P11388, Q13472, O95985, P04637, Q9H3D4, O15350, P60174, P09493,P07202, P12270, P56180, O43280, Q92519, Q96RU7, P19474, O15164, Q9UPN9,Q6AZZ1, P10155, P48995, Q13507, Q7Z4N2, Q7Z2W7, Q9HBA0, Q9BZW7, P01222,P16473, Q9H2G4, Q14166, Q8WZ42, P02766, P07437, O00294, Q15672, Q9P2K2,Q86VQ3, Q6A555, P14679, Q9BZF9, Q13404, Q14139, O95155, P11441, Q9UMX0,P17480, P09936, P15374, Q9Y3C8, P19224, P16662, P07911, Q8TCY9, Q9Y6N9,Q13107, P63027, Q15836, P18206, P55072, P21796, P08670, P04275, O75083,Q14191, P98170, Q13426, P13010, P12956, P67809, Q9Y2T7, O43829, Q13105,Q15915, O95409, Q8N9L1, Q9UDV7, Q9Y3S2, Q9UL40, Q14966, Q9H0M5, Q9Y5V0,Q96C28, Q9H5H4.

In a further preference, the peptide used for the inventive compound(e.g. peptide P or P_(a) or P_(b)) comprises an epitope or epitope part(e.g. at least two, preferably at least three, more preferably at leastfour, even more preferably at least five, yet even more preferably atleast six, especially at least seven or even at least eight amino acids)of one of the following histocompatibility antigens identified by theirUniProt accession code:

P04233, O15523, O14602, Q30201, P01891, P01892, P04439, P05534, P10314,P10316, P13746, P16188, P16189, P16190, P18462, P30443, P30447, P30450,P30453, P30455, P30456, P30457, P30459, P30512, Q09160, P01889, P03989,P10319, P18463, P18464, P18465, P30460, P30461, P30462, P30464, P30466,P30475, P30479, P30480, P30481, P30483, P30484, P30485, P30486, P30487,P30488, P30490, P30491, P30492, P30493, P30495, P30498, P30685, Q04826,Q29718, Q29836, Q29940, Q31610, Q31612, Q95365, P04222, P10321, P30499,P30501, P30504, P30505, P30508, P30510, Q07000, Q29865, Q29960, Q29963,Q95604, Q9TNN7, P28067, P28068, P06340, P13765, P20036, P04440, P01909,P01906, P01920, P05538, P01903, P01911, P01912, P04229, P13760, P13761,P20039, Q29974, Q30134, Q30167, Q5Y7A7, Q95IE3, Q9GIY3, Q9TQE0, P79483,P13762, Q30154, P13747, P30511, P17693, Q9BY66, Q29983, Q29980, P22090,Q03519, O14607, P08048.

In another preference, the peptide used for the inventive compound (e.g.peptide P or P_(a) or P_(b)) comprises an epitope or epitope part (e.g.at least two, preferably at least three, more preferably at least four,even more preferably at least five, yet even more preferably at leastsix, especially at least seven or even at least eight amino acids) of anAAV-antigen (such as an AAV capsid protein, see e.g. Example 10), inparticular wherein the AAV is one of AAV-8, AAV-9, AAV-6, AAV-2 orAAV-5, or of one of the following antigens of gene delivery vectorsidentified by their UniProt accession code:

A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362,P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8,Q8JQG0, Q98654, Q9WBP8, Q9YIJ1; preferably wherein the peptide comprisesthe AAV-8 capsid protein sequence LQQQNT (SEQ ID NO: 18), TTTGQNNNS (SEQID NO: 19) or GTANTQ (SEQ ID NO: 20).

In yet another preference, the peptide used for the inventive compound(e.g. peptide P or P_(a) or P_(b)) comprises an epitope or epitope part(e.g. at least two, preferably at least three, more preferably at leastfour, even more preferably at least five, yet even more preferably atleast six, especially at least seven or even at least eight amino acids)of an AAV-antigen (such as an AAV capsid protein, see e.g. Example 10),in particular wherein the AAV is one of AAV-8, AAV-9, AAV-6, AAV-2 orAAV-5, or of one of the following antigens of gene delivery vectorsidentified by their UniProt accession code:

A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362,P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8,Q8JQG0, Q98654, Q9WBP8, Q9YIJ1; preferably wherein the peptide comprisesthe AAV-8 capsid protein sequence LQQQNT (SEQ ID NO: 18), TTTGQNNNS (SEQID NO: 19) or GTANTQ (SEQ ID NO: 20).

In even yet another preference, the peptide used for the inventivecompound (e.g. peptide P or P_(a) or P_(b)) comprises an epitope orepitope part (e.g. at least two, preferably at least three, morepreferably at least four, even more preferably at least five, yet evenmore preferably at least six, especially at least seven or even at leasteight amino acids) of one of the following antigens of drugs/activeagents identified in Table 2:

Is an international non- proprietary Exemplary Sequence nameprescription Drug/Active agent available in (INN)? product AbciximabDrugBank YES Adalimumab DrugBank YES Aflibercept DrugBank YES Agalsidasebeta DrugBank YES Albiglutide DrugBank YES Albutrepenonacog alfaDrugBank YES Aldesleukin DrugBank YES Alglucosidase alfa DrugBank YESAnakinra DrugBank YES Asfotase Alfa DrugBank YES Atacicept DrugBank YESAtezolizumab DrugBank YES Becaplermin DrugBank YES Belatacept DrugBankYES Bevacizumab DrugBank YES Cerliponase alfa DrugBank YES CetuximabDrugBank YES Choriogonadotropin alfa DrugBank YES Denileukin diftitoxDrugBank YES Dulaglutide DrugBank YES Elapegademase DrugBank YESElosulfase alfa DrugBank YES Emicizumab DrugBank YES Eptacog alfaDrugBank YES Erenumab DrugBank YES Etanercept DrugBank YES FilgrastimDrugBank YES Galsulfase DrugBank YES Ibritumomab tiuxetan DrugBank YESIdarucizumab DrugBank YES Idursulfase DrugBank YES interferon alfa-2bDrugBank YES interferon alfacon-1 DrugBank YES Ipilimumab DrugBank YESIxekizumab DrugBank YES Laronidase DrugBank YES Lutropin alfa DrugBankYES Mecasermin DrugBank YES Metreleptin DrugBank YES Ofatumumab DrugBankYES Omalizumab DrugBank YES Oportuzumab monatox DrugBank YES OprelvekinDrugBank YES Palifermin DrugBank YES Pegademase DrugBank YES PegloticaseDrugBank YES Rasburicase DrugBank YES Rilonacept DrugBank YES RituximabDrugBank YES Romiplostim DrugBank YES Sebelipase alfa DrugBank YESTagraxofusp DrugBank YES Tasonermin DrugBank YES Thyrotropin alfaDrugBank YES Trastuzumab DrugBank YES Turoctocog alfa DrugBank YESAlpha-1- DrugBank Aralast NP proteinase inhibitor AntihemophilicDrugBank Hemofil M factor human Drotrecogin alfa DrugBank XigrisErythropoietin DrugBank Abseamed Follitropin DrugBank Bemfola Interferonalpha-1  DrugBank MultiferonT Interferon alpha-10 DrugBank MultiferonTInterferon alpha-14 DrugBank MultiferonT Interferon alpha-2  DrugBankMultiferonT Interferon alpha-21 DrugBank MultiferonT Interferon alpha-8 DrugBank MultiferonT Interferon beta-1a DrugBank Avonex interferongamma-1b DrugBank Actimmune Somatotropin DrugBank GentropinCorifollitropin alfa KEGG YES Efmoroctocog alfa KEGG YES Eftrenonacogalfa KEGG YES Evolocumab KEGG YES Natalizumab KEGG YES Taliglucerasealfa KEGG YES Teprotumumab KEGG YES Velmanase alpha UniProt O00754 YESFactor XIII UniProt P00488 Corifact (alpha and beta chain) & P05160 E.coli Asparaginase UniProt P00805 Elspar Antithrombin III UniProt P01008YES Beta-nerve growth UniProt P01138 factor (NGF) Parathyroid hormoneUniProt P01270 YES insulin UniProt P01308 YES Alglucerase UniProt P04062YES Von Willebrand UniProt P04275 Humate-P Factor Human Plasma proteaseUniProt P05155 Berinert C1 inhibitor Fibroblast growth UniProt P09038factor 2 (FGF2) Granulocyte colony- UniProt P09919 stimulating factor(G-CSF) Sphingomyelin UniProt P17405 phosphodiesterase Brain-derivedUniProt P23560 neurotrophic factor (BDNF) Glial cell line-derivedUniProt P39905 neurotrophic factor (GDNF) DrugBank(https://www.drugbank.ca/); KEGG: Kyoto Encyclopedia of Genes andGenomes (https://www.genome.jp/kegg/) .

The respective DrugBank and KEGG database accession numbers are listedbelow in Table 3 (DrugBank and KEGG database versions as of 20 Mar.2019):

ENZYMES DB00058 Alpha-1-proteinase inhibitor DB00088Ceredase/Alglucerase DB00053 Imiglucerase/Cerezyme D09675 Taliglucerasealfa (KEGG) DB00061 Pegademase Deaminase bovine DB00103 Agalsidase betaFabry DB01272 Alglucosidase alfa Pompe DB00090 Laronidasea-L-Iduronidase Hurler, MPS I DB01271 Idursulfase Iduronate-2-SulfataseM Hunter, MPS II DB09051 Elosulfase alfa N-Acetylgalactosamine-6Sulfatase Morquio Snydr A, MPS IVA DB01279 GalsulfaseN-Acetylgalactosamine-4 Sulfatase Maroteaux-Lamy, MPS VI DB11563Sebelipase alfa Lysosomal Acid Lipase Wolman, LAL Deficiency DB13173Cerliponase alfa Batten disease DB11563 Sebelipase alfa Lysosomal acidlipase deficiency (LAL-D) DB09105 Asfotase Alfa Perinatal/infantile- andjuvenile-onset hypophosphatasia (HPP) DB14712 Elapegademase Severecombined immunodeficiency disease (SCID) D10820 Olipudase alpha NiemannPick (KEGG) D11024 Velmanase alpha (alpha-Mannosidosis) DB00049Rasburicase (Elitec) urate-oxidase DB09208 Pegloticase (procine-likeuricase) COAGULATION FACTORS DB09109 Turoctocog alfa (modified FVIII)DB00055 Drotrecogin alfa activated human protein C DB13923 Emicizumabmimics FVIII DB00036 Coagulation factor VIIa DB00025 Antihemophilicfactor DB13133 Von Willebrand Factor Human (Vovendi) D10831 Susoctocogalfa (KEGG) DB00025 hu rec FVIII DB13152 Coagulation Factor IX HumanCYTOKINES: DB00038 Oprelvekin (rec IL11) DB00041 Aldesleukin (IL2)DB06372 Rilonacept (IL1-inhibitor) DB00026 Anakinra (IL1Ra) DB00004Denileukin diftitox DB00060 Interferon beta la DB05258 Interferon alphaDB00105 Interferon alpha 2b DB00069 Interferon alphacon 1 DB00033Interferon gamma-1b DB00034 Interferon Alfa-2a, Recombinant >HORMONES:DB00024 Thyrotropin alfa DB00097 Choriogonadotropin alfa DB00066Follitropin DB00044 Lutropin alfa DB00052 Somatotropin DB09043Albiglutide glucagon-like peptide-1 agonist (GLP-1) DB09046 Metreleptin(Leptin homologue) D08895 Corifollitropin alfa (KEGG) GROWTH FACTORS:DB00099 Filgrastim (G-CSF) DB01277 Mecasermin DB00039 Palifermin DB00102Becaplermin (PDGF) DB00039 Palifermin (KGF) DB11626 Tasonermin (TGFalpha) FUSION PROTEINS: DB08885 Aflibercept (VEGF-R/ Fc fusion) DB06372Rilonacept (IL-1R/Fc fusion) DB05332 Romiplostim (dimer Fc-pep fusion[peptibody], binding thrombopoietin rec) DB14731 Tag raxofusp (IL-3conjugated truncated diphtheria toxin) DB01281 Abatacept (Fc hingefusion to CTLA-4) D10830 Efmoroctocog alfa (FVIII-Fc fusion) (KEGG)D10522 Eftrenonacog alfa (human factor IX (FIX)-Fc fusion) (KEGG)DB06372 Rilonacept (IL-1R & IL-1R access prot Fc fusion) DB14731 Tagraxofusp (IL-3 conjugated truncated diphtheria toxin) DB06681 Belatacept(CTLA-4/Fc fusion) DB06399 Atacicept (extracellular ligand bindingportion of TACI) DB09043 GLP-1 receptor agonist-albumin fusion DB13884Albutrepenonacog alfa Recombinant factor IX albumin fusion (Idelvion)DB08885 Aflibercept VEGFR Fc-fusion (Zaltrap) DB09045 DulaglutideGlucagon like pep 1 receptor agonist Fc-fusion (Trulicity) DB06681Belatacept CTLA-4 Fc-fusion (Nulojix) DB08885 Aflibercept VEGFRFc-fusion (Eylea) DB00005 Etanercept Fc fusion FR Fc-fusion D10830Efmoroctocog alfa Rec F VIII Fc-fusion Elocta (KEGG) D10522 Eftrenonacogalfa Rec F IX Fc fusion (Alprolix) (KEGG) DB09105 Asfotase Alfa Fcfusion/enzyme asfotase-alfa [Strensiq] THERAPEUTIC mABs: D06886Natalizumab (KEGG) DB00073 Rituximab DB00051 Adalimumab/Humira DB06186Ipilimumab DB00072 Herceptin/Trastuzumab DB00112 Avastin/BevacizumabDB00005 Etanercept (Enbrel) D10557 Evolocumab (KEGG) DB11569 Ixekizumab(hulgG4 anti interleukin-17A) DB00043 Omalizumab D09680 Teprotumumab(KEGG) ANTIBODY-FRAGMENTS & DERIVATIVES: DB09264 Idarucizumab (Fab)DB00002 Cetuximab (epidermal growth factor receptor binding FAB) DB05319Oportuzumab monatox scFv-Toxin fusion DB00078 Ibritumomab (murine IgG1kappa) tiuxetan DB00054 Abciximab (chimaeric human/mouse mAB) DB00073Rituximab (hu IgG1 kappa) DB06650 Ofatumumab (hu IgG) DB14039 Erenumab(antag. calcitonin gene-rel pep. rec [CGRPR] migraine) DB13923Emicizumab (mimics the function of the coagulation Factor VIII) DB11595Atezolizumab (Fc-engineered, hum. mAB recognizing PD-L1) DB09264Idarucizumab - Fab (inactivates anticoagulant dabigatran)

Drugs/active agents on which the present invention can be applied (i.e.drugs/active agents leading to undesirable antibodies which can bedepleted by the compound of present invention) are also disclosed e.g.in Spiess et al 2015 and Runcie et al 2018. They may also be a scFv,Fab2, Fab3, Bis-scFv, bivalent minibody, diabody, triabody or tetrabody.Further, such drugs/active agents may be an affibody molecule (ProteinData Bank: 1LP1), affimer (Protein Data Bank: 1NB5), affitin molecule(Protein Data Bank: 4CJ2), anticalin molecule (Protein Data Bank: 4GH7),atrimer molecule (Protein Data Bank: 1TN3), fynomer (Protein Data Bank:1M27), armadillo repeat protein (Protein Data Bank: 4DB9), Kunitz domaininhibitor (Protein Data Bank: 1ZR0), knottin molecule (Protein DataBank: 2IT7), designed ankyrin repeat protein (Protein Data Bank: 2Q4J);Protein Databank (PDB) version as of 20 Mar. 2019. Further suitabledrugs/active agents are disclosed e.g. in WO 2017/220569 A1, WO2017/087589 A2, U.S. Pat. No. 82,100,547 and EP 1697421 A2 (inparticular SEQ ID NO: 1 thereof). As above, the peptide used for theinventive compound (e.g. peptide P or P_(a) or P_(b)) may comprise anepitope or epitope part (e.g. at least two, preferably at least three,more preferably at least four, even more preferably at least five, yeteven more preferably at least six, especially at least seven or even atleast eight amino acids) of the amino acid sequences of any one of thedrugs/active agents disclosed in the aforementioned sources.

It is also highly preferred that the peptides used for the inventivecompound do not bind to any HLA Class I or HLA Class II molecule (i.e.of the individual to be treated, e.g. human), in order to preventpresentation and stimulation via a T-cell receptor in vivo and therebyinduce an immune reaction. It is generally not desired to involve anysuppressive (or stimulatory) T-cell reaction in contrast toantigen-specific immunologic tolerization approaches. Therefore, toavoid T-cell epitope activity as much as possible, the peptides of thecompound of the present invention (e.g. peptide P or P_(a) or P_(b) orP₁ or P₂) preferably fulfil one or more of the followingcharacteristics:

-   -   To reduce the probability for a peptide used in the compound of        the present invention to bind to an HLA Class II or Class I        molecule, the peptide (e.g. peptide P or P_(a) or P_(b) or P₁ or        P₂) has a preferred length of 4-8 amino acids, although somewhat        shorter or longer lengths are still acceptable.    -   To further reduce the probability that such a peptide binds to        an HLA Class II or Class I molecule, it is preferred to test the        candidate peptide sequence by HLA binding prediction algorithms        such as NetMHCII-2.3 (reviewed by Jensen et al 2018).        Preferably, a peptide (e.g. peptide P or P_(a) or P_(b) or P₁ or        P₂) used in the compound of the present invention has        (predicted) HLA binding (IC50) of at least 500 nM. More        preferably, HLA binding (IC50) is more than 1000 nM, especially        more than 2000 nM (cf. e.g. Peters et al 2006). In order to        decrease the likelihood of HLA Class I binding, NetMHCpan 4.0        may also be applied for prediction (Jurtz et al 2017).    -   To further reduce the probability that such a peptide binds to        an HLA Class I molecule, the NetMHCpan Rank percentile        threshhold can be set to a background level of 10% according to        Koşaloğlu-Yalçin et al 2018 (PMID: 30377561). Preferably, a        peptide (e.g. peptide P or P_(a) or P_(b) or P₁ or P₂) used in        the compound of the present invention therefore has a % Rank        value of more than 3, preferably more than 5, more preferably        more than 10 according to the NetMHCpan algorithm.    -   To further reduce the probability that such a peptide binds to        an HLA Class II molecule, it is beneficial to perform in vitro        HLA-binding assays commonly used in the art such as for example        refolding assays, iTopia, peptide rescuing assays or array-based        peptide binding assays. Alternatively, or in addition thereto,        LC-MS based analytics can be used, as e.g. reviewed by Gfeller        et al 2016.

For stronger reduction of the titre of the undesired antibodies, it ispreferred that the peptides used in the present invention arecircularized (see also Example 4). Accordingly, in a preferredembodiment, at least one occurrence of P is a circularized peptide.Preferably at least 10% of all occurrences of P are circularizedpeptides, more preferably at least 25% of all occurrences of P arecircularized peptides, yet more preferably at least 50% of alloccurrences of P are circularized peptides, even more preferably atleast 75% of all occurrences of P are circularized peptides, yet evenmore preferably at least 90% of all occurrences of P are circularizedpeptides or even at least 95% of all occurrences of P are circularizedpeptides, especially all of the occurrences of P are circularizedpeptides. Several common techniques are available for circularization ofpeptides, see e.g. Ong et al 2017. It goes without saying that“circularized peptide” as used herein shall be understood as the peptideitself being circularized, as e.g. disclosed in Ong et al. (and not e.g.grafted on a circular scaffold with a sequence length that is longerthan 13 amino acids). Such peptides may also be referred to ascyclopeptides herein.

Further, for stronger reduction of the titre of the undesired antibodiesrelative to the amount of scaffold used, in a preferred embodiment ofthe compound of the present invention, independently for each of thepeptide n-mers, n is at least 2, more preferably at least 3, especiallyat least 4. Usually, in order to avoid complexities in the manufacturingprocess, independently for each of the peptide n-mers, n is less than10, preferably less than 9, more preferably less than 8, even morepreferably less than 7, yet even more preferably less than 6, especiallyless than 5. To benefit from higher avidity through divalent binding ofthe undesired antibody, it is highly preferred that, for each of thepeptide n-mers, n is 2.

For multivalent binding of the undesired antibodies, it is advantageousthat the peptide dimers or n-mers are spaced by a hydrophilic,structurally flexible, immunologically inert, non-toxic and clinicallyapproved spacer such as (hetero-)bifunctional and -trifunctionalPolyethylene glycol (PEG) spacers (e.g. NHS-PEG-Maleimide)—a wide rangeof PEG chains is available and PEG is approved by the FDA. Alternativesto PEG linkers such as immunologically inert and non-toxic syntheticpolymers or glycans are also suitable. Accordingly, in the context ofthe present invention, the spacer (e.g. spacer S) is preferably selectedfrom PEG molecules or glycans. For instance, the spacer such as PEG canbe introduced during peptide synthesis. Such spacers (e.g. PEG spacers)may have a molecular weight of e.g. 10000 Dalton. Evidently, within thecontext of the present invention, the covalent binding of the peptiden-mers to the biopolymer scaffold via a linker each may for example alsobe achieved by binding of the linker directly to a spacer of the peptiden-mer (instead of, e.g., to a peptide of the peptide n-mer).

Preferably, each of the peptide n-mers is covalently bound to thebiopolymer scaffold, preferably via a linker each.

As used herein, the linker may e.g. be selected from disulphide bridgesand PEG molecules.

According to a further preferred embodiment of the inventive compound,independently for each occurrence, P is P_(a) or P_(b).

Furthermore, it is preferred when in the first peptide n-mer, eachoccurrence of P is P_(a) and, in the second peptide n-mer, eachoccurrence of P is P_(b). Alternatively, or in addition thereto, P_(a)and/or P_(b) is circularized.

Divalent binding is particularly suitable to reduce antibody titres.According, in a preferred embodiment,

the first peptide n-mer is P_(a)-S-P_(a) and the second peptide n-mer isP_(a)-S-P_(a);

the first peptide n-mer is P_(a)-S-P_(a) and the second peptide n-mer isP_(b)-S-P_(b);

the first peptide n-mer is P_(b)-S-P_(b) and the second peptide n-mer isP_(b)-S-P_(b);

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(b);

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(a); or

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(b)-S-P_(b).

For increasing effectivity, in particular in autoimmune disease (whichis usually based on polyclonal antibodies, see above), in a preferredembodiment the first peptide n-mer is different from the second peptiden-mer. For similar reasons, preferably, the peptide P_(a) is differentfrom the peptide P_(b), preferably wherein the peptide P_(a) and thepeptide P_(b) are two different epitopes of the same antigen or twodifferent epitope parts of the same epitope.

Especially for better targeting of polyclonal antibodies, it isadvantageous when the peptide P_(a) and the peptide P_(b) comprise thesame amino-acid sequence fragment, wherein the amino-acid sequencefragment has a length of at least 2 amino acids, preferably at least 3amino acids, more preferably at least 4 amino acids, yet more preferablyat least 5 amino acids, even more preferably at least 6 amino acids, yeteven more preferably at least 7 amino acids, especially at least 8 aminoacids or even at least 9 amino acids.

Further, for stronger reduction of the titre of the undesired antibodiesrelative to the amount of scaffold used, the compound comprises aplurality of said first peptide n-mer (e.g. up to 10 or 20 or 30) and/ora plurality of said second peptide n-mer (e.g. up to 10 or 20 or 30).

For stronger reduction of the titre of the undesired antibodies relativeto the amount of scaffold used, the compound may also comprise at least

a third peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(c), wherein P_(c)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(c) is circularized;

a fourth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(d), wherein P_(d)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(d) is circularized;

a fifth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(e), wherein P_(e)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(e) is circularized;

a sixth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(f), wherein P_(f)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(f) is circularized;

a seventh peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(g), wherein P_(g)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(g) is circularized;

a eighth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(h), wherein P_(h)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(h) is circularized;

a ninth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(i), wherein P_(i)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(i) is circularized;

a tenth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(j), wherein P_(j)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(j) is circularized.

Peptides P_(c)-P_(j) may have one or more of same features (e.g.sequence) as disclosed herein for peptides P_(a) and P_(b).

As also illustrated above, it is highly preferred when the compound ofthe present invention is non-immunogenic in a mammal, preferably in ahuman, in a non-human primate, in a sheep, in a pig, in a dog or in arodent.

In the context of the present invention, a non-immunogenic compoundpreferably is a compound wherein the biopolymer scaffold (if it is aprotein) and/or the peptides (of the peptide n-mers) have an IC50 higherthan 100 nM, preferably higher than 500 nM, even more preferably higherthan 1000 nM, especially higher than 2000 nM, against HLA-DRB1_0101 aspredicted by the NetMHCII-2.3 algorithm. The NetMHCII-2.3 algorithm isdescribed in detail in Jensen et al, which is incorporated herein byreference. The algorithm is publicly available underhttp://www.cbs.dtu.dk/services/NetMHCII-2.3/. Even more preferably, anon-immunogenic compound (or pharmaceutical composition) does not bindto any HLA and/or MHC molecule (e.g. in a mammal, preferably in a human,in a non-human primate, in a sheep, in a pig, in a dog or in a rodent;or of the individual to be treated) in vivo.

According to a further preference, the compound is for intracorporealsequestration (or intracorporeal depletion) of at least one antibody inan individual, preferably in the bloodstream of the individual and/orfor reduction of the titre of at least one antibody in the individual,preferably in the bloodstream of the individual.

In another preferred embodiment, the entire sequence, optionally withthe exception of an N-terminal and/or C-terminal cysteine, of at leastone occurrence of P, preferably of at least 10% of all occurrences of P,more preferably of at least 25% of all occurrences of P, yet morepreferably of at least 50% of all occurrences of P, even more preferablyof at least 75% of all occurrences of P, yet even more preferably of atleast 90% of all occurrences of P or even of at least 95% of alloccurrences of P, especially of all of the occurrences of P, isidentical to a sequence fragment of a protein, wherein the protein isidentified by one of the UniProt accession codes disclosed herein;optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally withthe exception of an N-terminal and/or C-terminal cysteine, of peptideP_(a) is identical to a sequence fragment of a protein, wherein theprotein is identified by one of the UniProt accession codes disclosedherein; optionally wherein said sequence fragment comprises at mostfive, preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally withthe exception of an N-terminal and/or C-terminal cysteine, of peptideP_(b) is identical to a sequence fragment of a protein, wherein theprotein is identified by one of the UniProt accession codes disclosedherein; optionally wherein said sequence fragment comprises at mostfive, preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally withthe exception of an N-terminal and/or C-terminal cysteine, of peptideP_(a) is identical to a sequence fragment of a protein and the entiresequence, optionally with the exception of an N-terminal and/orC-terminal cysteine, of peptide P_(b) is identical to the same oranother, preferably another, sequence fragment of the same protein,wherein the protein is identified by one of the UniProt accession codeslisted herein; optionally wherein said sequence fragment and/or saidanother sequence fragment comprises at most five, preferably at mostfour, more preferably at most three, even more preferably at most two,especially at most one amino acid substitutions (e.g. for the purposesmentioned above, such as creating mimotopes).

Myasthenia gravis is an autoimmune neuromuscular disorder mediated byautoantibodies that cause a broad spectrum of several clinical symptomsfrom mild muscle weakness to a life-threatening myasthenic crisis withbreathing problems. Around 80% of myasthenic patients develop antinicotinic acetylcholine receptor (AChR) antibodies that lead tocomplement-mediated damaging of the postsynaptic membrane (Howard 2018),direct AChR blocking or receptor endocytosis. These disease-causingautoantibodies are mainly directed to defined immunogenic regions AChRor MuSK (Ruff 2018). They represent a good example for functionally wellcharacterized, disease-causing autoantibodies. Although generalimmunosuppressive or B-cell targeting strategies exist, a strategy isneeded whereby only diseases-causing antibodies (rather than all, mostlyprotective antibodies) are rapidly inactivated or depleted (especiallyin a myasthenic crisis), since neither of the generallyimmunosuppressive treatments with corticoids, IVIG, thymectomy or byplasma exchange are satisfactory. So far, no convenient therapeuticintervention exists that can deplete or neutralize disease causingantibodies in myasthenia gravis rapidly and selectively.

Rey et al. concerns the characterization of human antiacetylcholinereceptor monoclonal autoantibodies from the peripheral blood of amyasthenia gravis patient using combinatorial libraries.

EP 2698386 A1 relates to a fusion protein which is asserted tospecifically suppress autoantibodies such as autoantibodies involved inmyasthenia gravis. The fusion protein contains a binding site for theautoantibody and a fragment of the antibody heavy chain constant regionwhich exhibits antibody-dependent cellular cytotoxicity.

Non-selective B-cell targeting or immunotherapeutic approaches are notyet an established therapeutic option for the treatment of myastheniagravis. Alternatively, few intra- and extracorporeal selective antibodydepletion or B-cell suppression strategies targeting disease-causingantibodies in myasthenia gravis were proposed using indirect or directtargeting approaches against disease causing antibodies (see e.g. Homma2017 and Lazaridis 2017). In addition, an AChR-specificimmunosuppressive therapy using an adjuvanted AChR vaccine was proposed(Luo 2015). However, there remains an urgent need for a comparativelyeffective and safe and rapidly acting selective antibody depletiontherapy.

Accordingly, as mentioned in the summary, the present invention alsorelates to a compound (for use in the prevention or treatment ofmyasthenia gravis, especially in a myasthenic crisis), preferably forthe sequestration (or depletion) of anti human muscle nicotinicacetylcholine receptor (AChR) antibodies, anti human muscle-specificreceptor tyrosine kinase antibodies and/or anti human low-densitylipoprotein receptor related protein 4 antibodies present in a humanindividual, the compound comprising a biopolymer scaffold and at leasttwo peptides with a sequence length of 7-13 amino acids, wherein each ofthe peptides independently comprises a 7-13 amino-acid sequence fragmentof the AChR subunit alpha sequence identified by UniProt accession codeP02708 (optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)) or of the muscle-specificreceptor tyrosine kinase sequence identified by UniProt accession code015146 or of the low-density lipoprotein receptor related protein 4sequence identified by UniProt accession code 075096 (optionally whereinthe sequence fragment comprises at most five, preferably at most four,more preferably at most three, even more preferably at most two,especially at most one amino acid substitutions (e.g. such that amimotope is formed)), wherein the peptides are covalently bound to thebiopolymer scaffold, preferably via a linker, wherein the biopolymerscaffold is selected from the group consisting of human globulins andhuman albumin.

According to a particular preference, in particular for strongerreduction of the titre of the undesired antibodies relative to theamount of scaffold used, the at least two peptides comprise a peptide P₁and a peptide P₂, wherein P₁ and P₂ comprise the same 7-13 amino-acidsequence fragment of AChR subunit alpha (optionally wherein the sequencefragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions (e.g. such that a mimotope isformed)) or of the muscle-specific receptor tyrosine kinase or oflow-density lipoprotein receptor related protein 4 (optionally whereinthe sequence fragment comprises at most five, preferably at most four,more preferably at most three, even more preferably at most two,especially at most one amino acid substitutions (e.g. such that amimotope is formed)), wherein P₁ and P₂ are present in form of a peptidedimer P₁-S-P₂, wherein S is a non-peptide spacer, wherein the peptidedimer is covalently bound to the biopolymer scaffold, preferably via alinker.

Preferably, said 7-13 amino-acid sequence fragment of AChR subunit alphais a fragment of the sequence consisting of amino acids 21-255 of theAChR subunit alpha sequence identified by UniProt accession code P02708(optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)).

In a further preferred embodiment, said 7-13 amino-acid sequencefragment of AChR subunit alpha is a fragment of the sequenceLKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferably of the sequenceWNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3) (optionallywherein the sequence fragment comprises at most five, preferably at mostfour, more preferably at most three, even more preferably at most two,especially at most one amino acid substitutions (e.g. such that amimotope is formed)).

In a further preferred embodiment, the peptides have a sequence lengthof 8-13 amino acids, preferably 9-12 amino acids, more preferably 10-12amino acids, especially wherein the peptides consist of the sequenceVKKIHIPSEKG (SEQ ID NO: 4) optionally with an N-terminal and/orC-terminal cysteine residue, and/or optionally wherein the sequencefragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions (e.g. such that a mimotope isformed).

According to a further preferred embodiment, the compound furthercomprises at least one peptide with a sequence length of 7-13 aminoacids, wherein the at least one peptide comprises a 7-13 amino-acidsequence fragment of the muscle-specific receptor tyrosine kinasesequence identified by UniProt accession code 015146 or of thelow-density lipoprotein receptor related protein 4 sequence identifiedby UniProt accession code 075096, wherein the at least one peptide iscovalently bound to the biopolymer scaffold, preferably via a linker.

Furthermore, also for use in the prevention or treatment of myastheniagravis (especially in a myasthenic crisis), in a preferred embodiment ofinventive compound, at least one occurrence of P is P_(a) and at leastone occurrence of P is P_(b),

wherein P_(a) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein P_(b) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(a) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code P02708, O15146 or 075096, optionally wherein saidsequence fragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions,

-   -   wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(b) is        identical to a sequence fragment of a protein, wherein the        protein is identified by UniProt accession code P02708, O15146        or 075096, optionally wherein said sequence fragment comprises        at most five, preferably at most four, more preferably at most        three, even more preferably at most two, especially at most one        amino acid substitutions.

In embodiments, in particular for P_(a) and/or P_(b), said sequencefragment of the protein is a fragment of the sequence consisting ofamino acids 21-255 of the AChR subunit alpha sequence identified byUniProt accession code P02708 (optionally wherein the sequence fragmentcomprises at most five, preferably at most four, more preferably at mostthree, even more preferably at most two, especially at most one aminoacid substitutions (e.g. such that a mimotope is formed)). In furtherembodiments, in particular for Pa and/or Pb, said sequence fragment ofthe protein is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ IDNO: 1), preferably of the sequence WNPDDYGGVK (SEQ ID NO: 2) orVKKIHIPSEK (SEQ ID NO: 3). In particular, peptide Pa and/or peptide Pbconsist of the sequence VKKIHIPSEKG (SEQ ID NO: 4) optionally with anN-terminal and/or C-terminal cysteine residue.

Further, for stronger reduction of the titre of the undesired antibodiesrelated to myasthenia gravis, in a preferred embodiment, the firstpeptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(b).

Pre-eclampsia is an exemplary disease of pregnancy that involves notonly the placenta, but the entire organism. It occurs in 3-5% of allpregnancies predominantly in pregnant teens and women over 40 and itremains a leading cause of neonatal morbidity and mortality, typicallylater in pregnancy. An onset of hypertension in women that had nohistory of high blood pressure, elevated liver enzymes proteinuria,renal failure, low platelets (HELLP syndrome) and cerebral edema withseizures are hallmark of this condition. No specific cures are known,and the exact causes for preeclampsia appear to be complex. In general,therapeutic options are very limited.

Pathogenesis of preeclampsia involves abnormal placental implantation,placental hypoxia combined with the release of circulating factors,alterations of endothelial cell function and involvement of angiogenicfactors and inflammatory cytokines. Moreover, the renin angiotensinaldosterone system (RAAS) plays an important role in preeclampsia whichhas been corroborated by the finding that autoantibodies against theangiotensin II type 1-receptor (AT1-AA) contribute to the underlyingpathomechanism (Wallukat 1999).

The repertoire of preeclampsia-associated autoantibody specificities wasrecently extended e.g. to anti-alpha1-adrenoreceptors, prothrombin,anti-cardiolipin and more recently to GRP50 (Elliott 2016). Elliott andcolleagues found an antigenic mimicry mechanism: Preeclampsia patientsshowed antibody titers against a peptide epitope within the Epstein-Barrvirus nuclear antigen 1 (EBNA-1) that cross reacted with the placentalGPR50 membrane protein that is expressed in placental tissue. Antibodiesto the EBNA-1 antigen are also associated with several other autoimmunediseases such as Systemic Lupus Erythematosus, Multiple Sclerosis andmyalgic encephalitis/chronic fatigue syndrome.

Accordingly, as mentioned in the summary, the present invention alsorelates to a compound, preferably for the sequestration (or depletion)of anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibodies, antihuman melatonin-related receptor (GPR50) antibodies and/or anti humantype-1 angiotensin II receptor (AT1AR) antibodies present in a humanindividual, the compound comprising a biopolymer scaffold and at leasttwo peptides with a sequence length of 7-13 amino acids,

wherein each of the peptides independently comprises a 7-13 amino-acidsequence fragment of the EBNA1 sequence identified by UniProt accessioncode Q1HVF7 or P03211 or of the GPR50 sequence identified by UniProtaccession code Q13585 or of the type-1 angiotensin II receptor (AT1AR)sequence identified by UniProt accession code P30556, wherein thepeptides are covalently bound to the biopolymer scaffold,

wherein the biopolymer scaffold is selected from the group consisting ofhuman globulins, preferably from the group consisting of humanimmunoglobulins and human haptoglobin, and human albumin.

The compound can selectively reduce the levels of undesired antibodiesthat crossreact with a viral antigen (such as EBNA-1) and an endogenousmembrane receptor protein (such as GRP50).

According to a particular preference, in particular for strongerreduction of the titre of the undesired antibodies relative to theamount of scaffold used, the at least two peptides comprise a peptide P₁and a peptide P₂, wherein P₁ and P₂ comprise the same 7-13 amino-acidsequence fragment of said EBNA1 sequence or said GPR50 sequence or saidAT1AR sequence, wherein P₁ and P₂ are present in form of a peptide dimerP₁-S-P₂, wherein S is a non-peptide spacer, wherein the peptide dimer iscovalently bound to the biopolymer scaffold, preferably via a linker.

Preferably, said 7-13 amino-acid sequence fragment is a fragment of thesequence RPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO:6), preferably of the sequence KRPSCIGCK (SEQ ID NO: 7).

In a further preferred embodiment, said 7-13 amino-acid sequencefragment is a fragment of any one of the sequencesMILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO:9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), DVLIQLGIIRDCR (SEQID NO: 11), more preferably of the sequence AFHYESQ (SEQ ID NO: 12).

In a further preferred embodiment, the peptides have a sequence lengthof 8-13 amino acids, preferably 9-12 amino acids, more preferably 10-12amino acids, especially wherein at least one of the at least two,preferably each of the peptides consist of the sequence GRPQKRPSCIG (SEQID NO: 13) optionally with an N-terminal and/or C-terminal cysteineresidue.

According to a further preferred embodiment, the compound furthercomprises at least one peptide with a sequence length of 7-13 aminoacids, wherein the at least one peptide comprises a 7-13 amino-acidsequence fragment of the type-1 angiotensin II receptor (AT1AR) sequenceidentified by UniProt accession code P30556, preferably of any one ofthe sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8),TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ IDNO: 10), DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably of the sequenceAFHYESQ (SEQ ID NO: 12); wherein the at least one peptide is covalentlybound to the biopolymer scaffold, preferably via a linker.

Furthermore, also for use in the prevention or treatment ofpre-eclampsia, in a preferred embodiment of inventive compound, at leastone occurrence of P is P_(a) and at least one occurrence of P is P_(b),

wherein P_(a) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein P_(b) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(a) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code Q1HVF7, P03211, Q13585 or P30556, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(b) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code Q1HVF7, P03211, Q13585 or P30556, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions.

In embodiments, in particular for P_(a) and/or P_(b), said sequencefragment of the protein is a fragment of the sequence RPQKRPSCIGCKGTH(SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably of thesequence KRPSCIGCK (SEQ ID NO: 7). In further embodiments, in particularfor P_(a) and/or P_(b), said sequence fragment of the protein is afragment of any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ IDNO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP(SEQ ID NO: 10), DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably of thesequence AFHYESQ (SEQ ID NO: 12). In particular, peptide P_(a) and/orpeptide P_(b) consist of the sequence GRPQKRPSCIG (SEQ ID NO: 13)optionally with an N-terminal and/or C-terminal cysteine residue.

Further, for stronger reduction of the titre of the undesired antibodiesrelated to pre-eclampsia, in a preferred embodiment, the first peptiden-mer is P_(a)-S-P_(b) and the second peptide n-mer is P_(a)-S-P_(b).

Especially in the context of depleting undesired anti-drug antibodies,in yet another preferred embodiment of the present invention, the entiresequence, optionally with the exception of an N-terminal and/orC-terminal cysteine, of at least one occurrence of P, preferably of atleast 10% of all occurrences of P, more preferably of at least 25% ofall occurrences of P, yet more preferably of at least 50% of alloccurrences of P, even more preferably of at least 75% of alloccurrences of P, yet even more preferably of at least 90% of alloccurrences of P or even of at least 95% of all occurrences of P,especially of all of the occurrences of P, is identical to a sequencefragment of an amino-acid sequence of Alpha-1-proteinase inhibitor,Alglucerase, Taliglucerase alfa, Pegademase, Agalsidase beta,Alglucosidase alfa, Laronidase, Idursulfase, Elosulfase alfa,Galsulfase, Sebelipase alfa, Cerliponase alfa, Sebelipase alfa, AsfotaseAlfa, Elapegademase, Olipudase alpha, Velmanase alpha,N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,Pegloticase, Human Antithrombin III, Plasma protease C1 inhibitor,Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulation factor VIIaRecombinant Human, Antihemophilic factor human recombinant, VonWillebrand Factor Human, Susoctocog alfa, Antihemophilic factor humanrecombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab; optionally wherein said sequence fragmentcomprises at most five, preferably at most four, more preferably at mostthree, even more preferably at most two, especially at most one aminoacid substitutions.

Especially in the same context, in another preferred embodiment, theentire sequence, optionally with the exception of an N-terminal and/orC-terminal cysteine, of peptide P_(a) and/or P_(b) is identical to asequence fragment of an amino-acid sequence of Alpha-1-proteinaseinhibitor, Alglucerase, Taliglucerase alfa, Pegademase, Agalsidase beta,Alglucosidase alfa, Laronidase, Idursulfase, Elosulfase alfa,Galsulfase, Sebelipase alfa, Cerliponase alfa, Sebelipase alfa, AsfotaseAlfa, Elapegademase, Olipudase alpha, Velmanase alpha,N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,Pegloticase, Human Antithrombin III, Plasma protease C1 inhibitor,Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulation factor VIIaRecombinant Human, Antihemophilic factor human recombinant, VonWillebrand Factor Human, Susoctocog alfa, Antihemophilic factor humanrecombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab; optionally wherein said sequence fragmentcomprises at most five, preferably at most four, more preferably at mostthree, even more preferably at most two, especially at most one aminoacid substitutions.

Especially in the same context of anti-drug antibodies, in anotherpreferred embodiment, the entire sequence, the entire sequence,optionally with the exception of an N-terminal and/or C-terminalcysteine, of peptide P_(a) is identical to a sequence fragment of anamino-acid sequence and the entire sequence, optionally with theexception of an N-terminal and/or C-terminal cysteine, of peptide P_(b)is identical to the same or another, preferably another, sequencefragment of the same amino-acid sequence, wherein the amino-acidsequence is an amino-acid sequence of Alpha-1-proteinase inhibitor,Alglucerase, Taliglucerase alfa, Pegademase, Agalsidase beta,Alglucosidase alfa, Laronidase, Idursulfase, Elosulfase alfa,Galsulfase, Sebelipase alfa, Cerliponase alfa, Sebelipase alfa, AsfotaseAlfa, Elapegademase, Olipudase alpha, Velmanase alpha,N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,Pegloticase, Human Antithrombin III, Plasma protease C1 inhibitor,Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulation factor VIIaRecombinant Human, Antihemophilic factor human recombinant, VonWillebrand Factor Human, Susoctocog alfa, Antihemophilic factor humanrecombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab; optionally wherein said sequence fragmentand/or said another sequence fragment comprises at most five, preferablyat most four, more preferably at most three, even more preferably atmost two, especially at most one amino acid substitutions.

In an aspect, the present invention relates to a pharmaceuticalcomposition comprising the inventive and at least one pharmaceuticallyacceptable excipient.

In embodiments, the composition is prepared for intraperitoneal,subcutaneous, intramuscular and/or intravenous administration. Inparticular, the composition is for repeated administration (since it istypically non-immunogenic).

In a preference, the molar ratio of peptide P or P_(a) or P_(b) tobiopolymer scaffold in the composition is from 2:1 to 100:1, preferablyfrom 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferablyfrom 5:1 to 70:1, yet even more preferably from 6:1 to 60:1, especiallyfrom 7:1 to 50:1 or even from 8:10 to 40:1.

In another aspect, the compound of the present invention is for use intherapy.

Preferably, the compound is for use in prevention or treatment of anautoimmune disease in an individual having the autoimmune disease orbeing at risk of developing the autoimmune disease. These autoimmunediseases include neuromyelitis optica, seropositive neuromyelitis opticaspectrum disorders, autoimmune-encephalitis, multiple sclerosis,amyotrophic lateral sclerosis, systemic lupus erythematosus dementia,myasthenia gravis, in particular transient neonatal myasthenia gravis,dilatative Cardiomyopathy, pulmonary hypertension, Sjögren's Syndrome,celiac Disease, Graves Disease, Goodpasture Disease, preeclampsia,Behcet's Disease, systemic sclerosis, hypertension, type I diabetes,type II diabetes, systemic lupus erythematosus, antiN-methyl-D-aspartate receptor (NMDAR) encephalitis, antiphospholipidsyndrome, membranous nephropathy, primary biliary cholangitis,amyotrophic lateral sclerosis, Chagas disease cardiomyopathy, immunethrombocytopenic purpura, pemphigus vulgaris, bullous pemphigoid,epidermolysis bullosa acquisita and bullous systemic lupuserythematosus.

The compound of the present invention is also useful for prevention ortreatment of transplant rejection in an individual having a transplantor eligible for a transplantation.

In another embodiment, the compound is for use in prevention ortreatment of adverse reactions based on anti-drug antibodies oranti-gene-delivery vector antibodies, in particular anti-AAV antibodies,in an individual undergoing therapy with the drug or eligible fortherapy with the drug, or in an individual undergoing gene therapy oreligible for gene therapy,

Preferably wherein the drug is a peptide or protein, especially selectedfrom the group of enzymes, enzyme inhibitors, antibodies, antibodyfragments, antibody mimetics, antibody-drug conjugates, hormones, growthfactors, clotting factors and cytokines, preferably wherein the entiresequence, optionally with the exception of an N-terminal and/orC-terminal cysteine, of at least one occurrence of peptide P, or ofpeptide P_(a) and/or of peptide P_(b) is identical to a sequencefragment of an amino-acid sequence of the peptide or protein, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions. The drug may bee.g. any one of the drugs disclosed herein.

In embodiments, one or more antibodies are present in the individualwhich are specific for at least one occurrence of peptide P, or forpeptide P_(a) and/or peptide P_(b), preferably wherein said antibodiesare related to said disease.

It is highly preferred that the composition is non-immunogenic in theindividual (e.g. it does not comprise an adjuvant or animmunostimulatory substance that stimulates the innate or the adaptiveimmune system, e.g. such as an adjuvant or a T-cell epitope).

The composition of the present invention may be administered at a doseof 1-1000 mg, preferably 2-500 mg, more preferably 3-250 mg, even morepreferably 4-100 mg, especially 5-50 mg, compound per kg body weight ofthe individual, preferably wherein the composition is administeredrepeatedly. Such administration may be intraperitoneally,subcutaneously, intramuscularly or intravenously.

In an aspect, the present invention relates to a method of sequestering(or depleting) one or more antibodies present in an individual,comprising

-   -   obtaining a pharmaceutical composition as defined herein,        wherein the composition is non-immunogenic in the individual and        wherein the one or more antibodies present in the individual are        specific for at least one occurrence of P, or for peptide P_(a)        and/or peptide P_(b); and    -   administering (in particular repeatedly administering, e.g. at        least two times, preferably at least three times, more        preferably at least five times) the pharmaceutical composition        to the individual.

In the context of the present invention, the individual (to be treated)may be a non-human animal, preferably a non-human primate, a sheep, apig, a dog or a rodent, in particular a mouse.

Preferably, the biopolymer scaffold is autologous with respect to theindividual, preferably wherein the biopolymer scaffold is an autologousprotein (i.e. murine albumin is used when the individual is a mouse).

In embodiments, the individual is administered a heterologous protein,preferably a heterologous antibody such as a nanobody, and wherein theone or more antibodies present in the individual are specific for saidheterologous protein, preferably wherein said administering of theheterologous protein is prior to, concurrent with and/or subsequent tosaid administering of the pharmaceutical composition.

The heterologous protein (in particular a human or humanized antibody)may for instance be for therapy (in particular immunotherapy) of amalignancy or a cancer. In embodiments, the individual may have themalignancy or the cancer and may e.g. be treated or eligible to betreated or designated to be treated with the heterologous protein suchas the antibody.

In a preference, the individual is a non-human animal and theheterologous protein is human or humanized such as a human or humanizedantibody (e.g. for preclinical testing of a human or humanizedbiological such as a monoclonal antibody).

In a further preference, the individual is administered a drug andwherein the one or more antibodies present in the individual arespecific for said drug, preferably wherein said administering of thedrug is prior to, concurrent with and/or subsequent to saidadministering of the pharmaceutical composition.

The drug may be any drug as disclosed herein.

In embodiments, the individual is healthy.

In another aspect, the present invention relates to a pharmaceuticalcomposition, comprising the compound of the present invention andfurther comprising an active agent such as a protein or a peptide andoptionally at least one pharmaceutically acceptable excipient, whereinthe active agent comprises a peptide fragment with a sequence length of2-13 amino acids, preferably 3-11 amino acids, more preferably 4-9 aminoacids, especially 5-8 amino acids, and wherein the sequence of at leastone occurrence of peptide P, or peptide P_(a) and/or peptide P_(b), ofthe compound is at least 70% identical, preferably at least 75%identical, more preferably at least 80% identical, yet more preferablyat least 85% identical, even more preferably at least 90% identical, yeteven more preferably at least 95% identical, especially completelyidentical to the sequence of said peptide fragment.

The active agent may be an enzyme, preferably a human enzyme, anantibody, preferably a human or humanized antibody, a hormone, a growthfactor, a clotting factor, a cytokine or a gene delivery vector (such asAAV), in particular as disclosed herein.

This composition is preferably for use in inhibition of an immunereaction, preferably an antibody-mediated immune reaction, against theactive agent.

This composition is furthermore preferably non-immunogenic in theindividual.

In yet another aspect, the present invention relates to a method ofinhibiting an immune reaction to a treatment with an active agent in anindividual in need of treatment with the active agent, comprisingobtaining a pharmaceutical composition as defined above; wherein thecompound of the pharmaceutical composition is non-immunogenic in theindividual, and administering (preferably repeatedly administering) thepharmaceutical composition to the individual.

In yet even another aspect, the present invention relates to a method ofproviding the compound of the invention, comprising the steps ofidentifying at least one individual having an undesired antibody againstan antigen, screening a peptide library to identify a peptide mimotopefor which the undesired antibody is specific, and providing thecompound, wherein at least one occurrence of P of the compound comprisesthe entire sequence of the peptide mimotope. In this aspect, thecompound can be regarded as mimotope-based compound. Mimotopes aredescribed hereinabove. See also Example 4. In general, screening forpeptide mimotopes per se is known in the art, see for instance Shanmugamet al.

Mimotope-based compounds of the invention have the following twoadvantages over compounds based on wild-type epitopes: First, theundesired antibodies, as a rule, have even higher affinities formimotopes found by screening a peptide library, leading to higherclearance efficiency of the mimotope-based compound. Second, mimotopesfurther enable avoiding T-cell epitope activity as much as possible (asdescribed hereinabove) in case the wild-type epitope sequence inducessuch T-cell epitope activity.

In a preference, at least 10% of all occurrences of P of the compoundcomprise the entire sequence of the peptide mimotope, more preferablywherein at least 25% of all occurrences of P comprise the entiresequence of the peptide mimotope, yet more preferably wherein at least50% of all occurrences of P comprise the entire sequence of the peptidemimotope, even more preferably wherein at least 75% of all occurrencesof P comprise the entire sequence of the peptide mimotope, yet even morepreferably wherein at least 90% of all occurrences of P comprise theentire sequence of the peptide mimotope or even wherein at least 95% ofall occurrences of P comprise the entire sequence of the peptidemimotope, especially wherein all of the occurrences of P comprise theentire sequence of the peptide mimotope.

In embodiments, the antigen may be a peptide or protein, wherein thesequence of the peptide or protein does not comprise the entire sequenceof the peptide mimotope. In other words, the sequence of the peptidemimotope and the wildtype epitope (as found on the peptide or protein)differs in at least one amino acid.

In an especially preferred embodiment, the peptide library comprisescircular peptides, as they typically have an even higher affinity to theundesired antibody (see Example 4). The peptide library may e.g. be aphage display library, a peptide microarray library or a soluble peptidelibrary.

In a further preferred embodiment, the screening of the peptide libraryis performed with a serum obtained from the at least one individual,wherein the serum comprises the undesired antibody. See for instanceGazarian et al. or Leung et al. on how to perform a serum-based screenfor mimotopes.

In embodiments, the compound preferably is non-immunogenic in the atleast one individual.

In further embodiments, the at least one individual is a non-humananimal, preferably a non-human primate, a sheep, a pig, a dog or arodent, in particular a mouse. The at least one individual may also behuman.

In yet another preferred embodiment, the biopolymer scaffold isautologous with respect to the at least one individual, preferablywherein the biopolymer scaffold is an autologous protein.

In embodiments, the at least one individual has been administered aheterologous protein, preferably a heterologous antibody such as ananobody, and wherein the antigen is said heterologous protein.

In another embodiment, the at least one individual is a non-human animaland the heterologous protein is human or humanized, such as for instanceduring the development of human or humanized antibodies.

In a further preference, the individual has been administered a drug andthe drug is the antigen. The drug may be an enzyme, preferably a humanenzyme, an antibody, preferably a human or humanized antibody, ahormone, a growth factor, a clotting factor, a cytokine or a genedelivery vector such as AAV, e.g. as defined herein. For instance, thedrug may be Alpha-1-proteinase inhibitor, Alglucerase, Taliglucerasealfa, Pegademase, Agalsidase beta, Alglucosidase alfa, Laronidase,Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa, Cerliponasealfa, Sebelipase alfa, Asfotase Alfa, Elapegademase, Olipudase alpha,Velmanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase,Rasburicase, Pegloticase, Human Antithrombin III, Plasma protease C1inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulationfactor VIIa Recombinant Human, Antihemophilic factor human recombinant,Von Willebrand Factor Human, Susoctocog alfa, Antihemophilic factorhuman recombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab.

In embodiments, the individual may be healthy.

According to a further preferred embodiment, the undesired antibody maybe an autoantibody of the at least one individual.

In the context of the present invention, for improved bioavailability,it is preferred that the inventive compound has a solubility in water at25° C. of at least 0.1 μg/ml, preferably at least 1 μg/ml, morepreferably at least 10 μg/ml, even more preferably at least 100 μg/ml,especially at least 1000 μg/ml.

The term “preventing” or “prevention” as used herein means to stop adisease state or condition from occurring in a patient or subjectcompletely or almost completely or at least to a (preferablysignificant) extent, especially when the patient or subject orindividual is predisposed to such a risk of contracting a disease stateor condition.

The pharmaceutical composition of the present invention is preferablyprovided as a (typically aqueous) solution, (typically aqueous)suspension or (typically aqueous) emulsion. Excipients suitable for thepharmaceutical composition of the present invention are known to theperson skilled in the art, upon having read the present specification,for example water (especially water for injection), saline, Ringer'ssolution, dextrose solution, buffers, Hank solution, vesicle formingcompounds (e.g. lipids), fixed oils, ethyl oleate, 5% dextrose insaline, substances that enhance isotonicity and chemical stability,buffers and preservatives. Other suitable excipients include anycompound that does not itself induce the production of antibodies in thepatient (or individual) that are harmful for the patient (orindividual). Examples are well tolerable proteins, polysaccharides,polylactic acids, polyglycolic acid, polymeric amino acids and aminoacid copolymers. This pharmaceutical composition can (as a drug) beadministered via appropriate procedures known to the skilled person(upon having read the present specification) to a patient or individualin need thereof (i.e. a patient or individual having or having the riskof developing the diseases or conditions mentioned herein). Thepreferred route of administration of said pharmaceutical composition isparenteral administration, in particular through intraperitoneal,subcutaneous, intramuscular and/or intravenous administration. Forparenteral administration, the pharmaceutical composition of the presentinvention is preferably provided in injectable dosage unit form, e.g. asa solution (typically as an aqueous solution), suspension or emulsion,formulated in conjunction with the above-defined pharmaceuticallyacceptable excipients. The dosage and method of administration, however,depends on the individual patient or individual to be treated. Saidpharmaceutical composition can be administered in any suitable dosageknown from other biological dosage regimens or specifically evaluatedand optimised for a given individual. For example, the active agent maybe present in the pharmaceutical composition in an amount from 1 mg to10 g, preferably 50 mg to 2 g, in particular 100 mg to 1 g. Usualdosages can also be determined on the basis of kg body weight of thepatient, for example preferred dosages are in the range of 0.1 mg to 100mg/kg body weight, especially 1 to 10 mg/kg body weight (peradministration session). The administration may occur e.g. once daily,once every other day, once per week or once every two weeks. As thepreferred mode of administration of the inventive pharmaceuticalcomposition is parenteral administration, the pharmaceutical compositionaccording to the present invention is preferably liquid or ready to bedissolved in liquid such sterile, de-ionised or distilled water orsterile isotonic phosphate-buffered saline (PBS). Preferably, 1000 μg(dry-weight) of such a composition comprises or consists of 0.1-990 μg,preferably 1-900 μg, more preferably 10-200 μg compound, and option-ally1-500 μg, preferably 1-100 μg, more preferably 5-15 μg (buffer) salts(preferably to yield an isotonic buffer in the final volume), andoptionally 0.1-999.9 μg, preferably 100-999.9 μg, more preferably200-999 μg other excipients. Preferably, 100 mg of such a drycomposition is dissolved in sterile, de-ionised/distilled water orsterile isotonic phosphate-buffered saline (PBS) to yield a final volumeof 0.1-100 ml, preferably 0.5-20 ml, more preferably 1-10 ml.

It is evident to the skilled person that active agents and drugsdescribed herein can also be administered in salt-form (i.e. as apharmaceutically acceptable salt of the active agent). Accordingly, anymention of an active agent herein shall also include anypharmaceutically acceptable salt forms thereof.

Methods for chemical synthesis of peptides used for the compound of thepresent invention are well-known in the art. Of course, it is alsopossible to produce the peptides using recombinant methods. The peptidescan be produced in microorganisms such as bacteria, yeast or fungi, ineukaryotic cells such as mammalian or insect cells, or in a recombinantvirus vector such as adenovirus, poxvirus, herpesvirus, Simliki forestvirus, baculovirus, bacteriophage, sindbis virus or sendai virus.Suitable bacteria for producing the peptides include E. coli, B.subtilis or any other bacterium that is capable of expressing suchpeptides. Suitable yeast cells for expressing the peptides of thepresent invention include Saccharomyces cerevisiae, Schizosaccharomycespombe, Candida, Pichiapastoris or any other yeast capable of expressingpeptides. Corresponding means and methods are well known in the art.Also, methods for isolating and purifying recombinantly producedpeptides are well known in the art and include e.g. gel filtration,affinity chromatography, ion exchange chromatography etc.

Beneficially, cysteine residues are added to the peptides at the N-and/or C-terminus to facilitate coupling to the biopolymer scaffold,especially.

To facilitate isolation of said peptides, fusion polypeptides may bemade wherein the peptides are translationally fused (covalently linked)to a heterologous polypeptide which enables isolation by affinitychromatography. Typical heterologous polypeptides are His-Tag (e.g.His6; 6 histidine residues), GST-Tag (Glutathione-S-transferase) etc.The fusion polypeptide facilitates not only the purification of thepeptides but can also prevent the degradation of the peptides during thepurification steps. If it is desired to remove the heterologouspolypeptide after purification, the fusion polypeptide may comprise acleavage site at the junction between the peptide and the heterologouspolypeptide. The cleavage site may consist of an amino acid sequencethat is cleaved with an enzyme specific for the amino acid sequence atthe site (e.g. proteases).

The coupling/conjugation chemistry used to link the peptides/peptiden-mers to the biopolymer scaffold (e.g. via heterobifunctional compoundssuch as GMBS and of course also others as described in “BioconjugateTechniques”, Greg T. Hermanson) or used to conjugate the spacer to thepeptides in the context of the present invention can also be selectedfrom reactions known to the skilled in the art. The biopolymer scaffolditself may be recombinantly produced or obtained from natural sources.

Herein, the term “specific for”—as in “molecule A specific for moleculeB”—means that molecule A has a binding preference for molecule Bcompared to other molecules in an individual's body. Typically, thisentails that molecule A (such as an antibody) has a dissociationconstant (also called “affinity”) in regard to molecule B (such as theantigen, specifically the binding epitope thereof) that is lower than(i.e. “stronger than”) 1000 nM, preferably lower than 100 nM, morepreferably lower than 50 nM, even more preferably lower than 10 nM,especially lower than 5 nM.

Herein, “UniProt” refers to the Universal Protein Resource. UniProt is acomprehensive resource for protein sequence and annotation data. UniProtis a collaboration between the European Bioinformatics Institute(EMBL-EBI), the SIB Swiss Institute of Bioinformatics and the ProteinInformation Resource (PIR). Across the three institutes more than 100people are involved through different tasks such as database curation,software development and support. Website: http://www.uniprot.org/

Entries in the UniProt databases are identified by their accession codes(referred to herein e.g. as “UniProt accession code” or briefly as“UniProt” followed by the accession code), usually a code of sixalphanumeric letters (e.g. “Q1HVF7”). If not specified otherwise, theaccession codes used herein refer to entries in the ProteinKnowledgebase (UniProtKB) of UniProt. If not stated otherwise, theUniProt database state for all entries referenced herein is of 13 Feb.2019 (UniProt/UniProtKB Release 2019_02).

In the context of the present application, sequence variants (designatedas “natural variant” in UniProt) are expressly included when referringto a UniProt database entry.

“Percent (%) amino acid sequence identity” or “X % identical” (such as“70% identical”) with respect to a reference polypeptide or proteinsequence is defined as the percentage of amino acid residues in acandidate sequence that are identical with the amino acid residues inthe reference polypeptide sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequenceidentity, and not considering any conservative substitutions as part ofthe sequence identity. Alignment for purposes of determining percentamino acid sequence identity can be achieved in various ways that arewithin the skill in the art, for instance, using publicly availablecomputer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, Megalign(DNASTAR) or the “needle” pairwise sequence alignment application of theEMBOSS software package. Those skilled in the art can determineappropriate parameters for aligning sequences, including any algorithmsneeded to achieve maximal alignment over the full length of thesequences being compared. For purposes herein, however, % amino acidsequence identity values are calculated using the sequence alignment ofthe computer programme “needle” of the EMBOSS software package (publiclyavailable from European Molecular Biology Laboratory; Rice et al.,EMBOSS: the European Molecular Biology Open Software Suite, TrendsGenet. 2000 June; 16(6):276-7, PMID: 10827456).

The needle programme can be accessed under the web sitehttp://www.ebi.ac.uk/Tools/psa/emboss_needle/or downloaded for localinstallation as part of the EMBOSS package fromhttp://emboss.sourceforge.net/. It runs on many widely-used UNIXoperating systems, such as Linux.

To align two protein sequences, the needle programme is preferably runwith the following parameters:

Commandline: needle-auto-stdout-asequence SEQUENCE_FILE A—bsequenceSEQUENCE_FILE B—datafile EBLOSUM62—gapopen 10.0—gapextend 0.5—endopen10.0—endextend 0.5—aformat3 pair—sprotein1—sprotein2 (Align_format: pairReport file: stdout)

The % amino acid sequence identity of a given amino acid sequence A to,with, or against a given amino acid sequence B (which can alternativelybe phrased as a given amino acid sequence A that has or comprises acertain % amino acid sequence identity to, with, or against a givenamino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matchesby the sequence alignment program needle in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. In cases where “the sequence of A is more than N %identical to the entire sequence of B”, Y is the entire sequence lengthof B (i.e. the entire number of amino acid residues in B). Unlessspecifically stated otherwise, all % amino acid sequence identity valuesused herein are obtained as described in the immediately precedingparagraph using the needle computer program.

The present invention further relates to the following embodiments:

Embodiment 1. A compound comprising

-   -   a biopolymer scaffold and at least    -   a first peptide n-mer of the general formula:

P(-S-P)_((n-1)) and

-   -   a second peptide n-mer of the general formula: P(-S-P)_((n-1));

wherein, independently for each occurrence, P is a peptide with asequence length of 2-13 amino acids, preferably 3-11 amino acids, morepreferably 4-9 amino acids, especially 5-8 amino acids, and S is anon-peptide spacer,

wherein, independently for each of the peptide n-mers, n is an integerof at least 1, preferably of at least 2, more preferably of at least 3,especially of at least 4,

wherein each of the peptide n-mers is bound to the biopolymer scaffold,preferably via a linker each.

Embodiment 2. The compound of embodiment 1, wherein at least oneoccurrence of P is a circularized peptide, preferably wherein at least10% of all occurrences of P are circularized peptides, more preferablywherein at least 25% of all occurrences of P are circularized peptides,yet more preferably wherein at least 50% of all occurrences of P arecircularized peptides, even more preferably wherein at least 75% of alloccurrences of P are circularized peptides, yet even more preferablywherein at least 90% of all occurrences of P are circularized peptidesor even wherein at least 95% of all occurrences of P are circularizedpeptides, especially wherein all of the occurrences of P arecircularized peptides.Embodiment 3. The compound of embodiment 1 or 2, wherein, independentlyfor each of the peptide n-mers, n is at least 2, more preferably atleast 3, especially at least 4.Embodiment 4. The compound of any one of embodiments 1 to 3, wherein,independently for each of the peptide n-mers, n is less than 10,preferably less than 9, more preferably less than 8, even morepreferably less than 7, yet even more preferably less than 6, especiallyless than 5.Embodiment 5. The compound of any one of embodiments 1 to 4, wherein,for each of the peptide n-mers, n is 2.Embodiment 6. The compound of any one of embodiments 1 to 5, wherein atleast one occurrence of P is P_(a) and/or at least one occurrence of Pis P_(b),

wherein P_(a) is a peptide with a sequence length of 2-13 amino acids,preferably 3-11 amino acids, more preferably 4-9 amino acids, especially5-8 amino acids,

wherein P_(b) is a peptide with a sequence length of 2-13 amino acids,preferably 3-11 amino acids, more preferably 4-9 amino acids, especially5-8 amino acids.

Embodiment 7. The compound of any one of embodiments 1 to 6, wherein,independently for each occurrence, P is P_(a) or P_(b).Embodiment 8. The compound of any one of embodiments 1 to 7, wherein, inthe first peptide n-mer, each occurrence of P is P_(a) and, in thesecond peptide n-mer, each occurrence of P is P_(b).Embodiment 9. The compound of any one of embodiments 1 to 8, wherein

the first peptide n-mer is P_(a)-S-P_(a) and the second peptide n-mer isP_(a)-S-P_(a); or

the first peptide n-mer is P_(a)-S-P_(a) and the second peptide n-mer isP_(b)-S-P_(b);

the first peptide n-mer is P_(b)-S-P_(b) and the second peptide n-mer isP_(b)-S-P_(b);

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(b);

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(a); or

the first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(b)-S-P_(b).

Embodiment 10. A compound comprising

a biopolymer scaffold and at least

a first peptide n-mer which is a peptide dimer of the formulaP_(a)-S-P_(a) or P_(a)-S-P_(b),

wherein P_(a) is a peptide with a sequence length of 2-13 amino acids,preferably 3-11 amino acids, more preferably 4-9 amino acids, especially5-8 amino acids, P_(b) is a peptide with a sequence length of 2-13 aminoacids, preferably 3-11 amino acids, more preferably 4-9 amino acids,especially 5-8 amino acids, and S is a non-peptide spacer,

-   -   wherein the first peptide n-mer is bound to the biopolymer        scaffold, preferably via a linker.        Embodiment 11. The compound of embodiment 10, further comprising        a second peptide n-mer which is a peptide dimer of the formula        P_(b)-S-P_(b) or P_(a)-S-P_(b),

wherein the second peptide n-mer is bound to the biopolymer scaffold,preferably via a linker.

Embodiment 12. The compound of any one of embodiments 1 to 9 and 11,wherein the first peptide n-mer is different from the second peptiden-mer.Embodiment 13. The compound of any one of embodiments 6 to 12, whereinthe peptide P_(a) is different from the peptide P_(b), preferablywherein the peptide P_(a) and the peptide P_(b) are two differentepitopes of the same antigen or two different epitope parts of the sameepitope.Embodiment 14. The compound of any one of embodiments 6 to 13, whereinthe peptide P_(a) and the peptide P_(b) comprise the same amino-acidsequence fragment, wherein the amino-acid sequence fragment has a lengthof at least 2 amino acids, preferably at least 3 amino acids, morepreferably at least 4 amino acids, yet more preferably at least 5 aminoacids, even more preferably at least 6 amino acids, yet even morepreferably at least 7 amino acids, especially at least 8 amino acids oreven at least 9 amino acids.Embodiment 15. The compound of any one of embodiments 6 to 14, whereinP_(a) and/or P_(b) is circularized.Embodiment 16. The compound of any one of embodiments 1 to 15, whereinthe compound comprises a plurality of said first peptide n-mer and/or aplurality of said second peptide n-mer.Embodiment 17. The compound of any one of embodiments 1 to 16, whereinthe biopolymer scaffold is a protein, preferably a mammalian proteinsuch as a human protein, a non-human primate protein, a sheep protein, apig protein, a dog protein or a rodent protein.Embodiment 18. The compound of embodiment 17, wherein the biopolymerscaffold is a globulin.Embodiment 19. The compound of embodiment 18, wherein the biopolymerscaffold is selected from the group consisting of immunoglobulins,alpha1-globulins, alpha2-globulins and beta-globulins.Embodiment 20. The compound of embodiment 19, wherein the biopolymerscaffold is selected from the group consisting of immunoglobulin G,haptoglobin and transferrin.Embodiment 21. The compound of embodiment 20, wherein the biopolymerscaffold is haptoglobin.Embodiment 22. The compound of embodiment 17, wherein the biopolymerscaffold is an albumin.Embodiment 23. The compound of any one of embodiments 1 to 22, whereinthe compound is non-immunogenic in a mammal, preferably in a human, in anon-human primate, in a sheep, in a pig, in a dog or in a rodent.Embodiment 24. The compound of any one of embodiments 1 to 23, whereinthe compound is for intracorporeal sequestration (or intracorporealdepletion) of at least one antibody in an individual, preferably in thebloodstream of the individual and/or for reduction of the titre of atleast one antibody in the individual, preferably in the bloodstream ofthe individual.Embodiment 25. The compound of any one embodiments 1 to 24, wherein thecompound further comprises at least

a third peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(c), wherein P_(c)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(c) is circularized;

a fourth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(d), wherein P_(d)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(d) is circularized;

a fifth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(e), wherein P_(e)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(e) is circularized;

a sixth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(f), wherein P_(f)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(f) is circularized;

a seventh peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(g), wherein P_(g)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(g) is circularized;

a eighth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(h), wherein P_(h)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(h) is circularized;

a ninth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P₁, wherein P_(i) is        a peptide with a sequence length of 2-13 amino acids, preferably        3-11 amino acids, more preferably 4-9 amino acids, especially        5-8 amino acids,    -   more preferably wherein P_(i) is circularized;

a tenth peptide n-mer of the general formula:

P(-S-P)_((n-1)),

-   -   wherein, independently for each occurrence, P is a peptide with        a sequence length of 2-13 amino acids, preferably 3-11 amino        acids, more preferably 4-9 amino acids, especially 5-8 amino        acids, and S is a non-peptide spacer,    -   preferably wherein each occurrence of P is P_(j), wherein P_(j)        is a peptide with a sequence length of 2-13 amino acids,        preferably 3-11 amino acids, more preferably 4-9 amino acids,        especially 5-8 amino acids,    -   more preferably wherein P_(j) is circularized.        Embodiment 26. The compound of any one of embodiments 1 to 25,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of at least one        occurrence of P, preferably of at least 10% of all occurrences        of P, more preferably of at least 25% of all occurrences of P,        yet more preferably of at least 50% of all occurrences of P,        even more preferably of at least 75% of all occurrences of P,        yet even more preferably of at least 90% of all occurrences of P        or even of at least 95% of all occurrences of P, especially of        all of the occurrences of P, is identical to a sequence fragment        of a protein, wherein the protein is identified by one of the        following UniProt accession codes:        P01023, A8K2U0, P49588, Q5JTZ9, O95477, Q8IZY2, P08183, P33527,        O15438, Q961U4, P00519, P42684, Q9BYF1, P22303, Q99798, P68133,        P60709, P63261, P12814, O43707, P61158, Q13705, P37023, O75077,        Q9UKQ2, Q76LX8, Q6ZMM2, P35611, P07327, P00325, P35348, P25100,        P08588, P07550, P25098, P35626, P30566, P43652, P02771, Q5U5Z8,        Q15109, P35573, Q9UL18, Q9UKV8, O00468, P01019, P30556, Q09666,        P02765, O43918, Q9Y6K8, Q02952, P14550, P15121, O95154, P02768,        P00352, P49189, Q9UM73, P09923, P05187, P03971, P49418, P03950,        Q9BY76, Q15327, P15144, P04083, P50995, P07355, Q3ZCQ2, P12429,        P09525, P08758, P08133, O76027, Q13367, P27695, Q9BZZ5, P02647,        P04114, P02749, P05067, P29972, P55087, Q8N726, P05089, Q9UNA1,        P52566, Q99819, Q15052, P07306, P04424, P08243, Q9BXN1, P15336,        P13637, P05026, P98194, P20648, P51164, P06576, P48047, P54252,        Q8WXX7, P01185, P25311, Q9H6S1, P61769, Q13072, O75531, Q99728,        P10415, P41182, P11274, O14503, Q93088, O00499, O15392, P35226,        P12643, P18075, Q8N8U9, Q13873, P17213, Q9NP55, Q96DR5, Q8TDL5,        P15056, Q7Z569, P38398, P51587, Q58F21, Q8IWQ3, Q8NE79, Q9Y224,        Q13901, P02745, P01024, P00915, P00918, P07451, O00555, Q00975,        Q9NY47, Q9Y698, Q8TC20, Q05682, P27482, P27797, P27824, P04632,        P52907, P42574, Q14790, P31415, P41180, P20810, O15446, P04040,        Q9NTU7, Q5M9NO, Q3V6T2, P10147, P13501, P20248, P14635, P24385,        Q8ND76, P51681, P49368, P48643, P50990, Q9NZQ7, P28906, P16671,        P04234, P15529, P08174, P13987, P01732, P21926, P30305, P12830,        P55291, P22223, P55283, P06493, P42771, P51861, Q01850, Q9H211,        P13688, P06731, Q9UNI1, P49450, P07199, Q03188, Q02224, P49454,        Q9H3R5, Q92674, Q6IPU0, Q7L2Z9, A8MT69, Q5JTW2, P00751, P08603,        Q03591, P36980, Q02985, Q9P2M7, O95992, Q14839, P10645, P36222,        Q15782, Q9UKJ5, Q9Y259, P11229, P08172, P20309, P08173, P08912,        P02708, Q9UGM1, P11230, Q8NCH0, Q99828, O75339, Q14011, Q07065,        P12277, Q96MX0, P06732, A8K714, O95832, O75508, P30622, Q96KN2,        Q12860, Q02246, Q8IWV2, O94779, Q9UQ52, P78357, Q9UHC6, Q7Z7A1,        P38432, Q5TAT6, Q9UMD9, P02452, Q01955, P29400, Q14031, P12111,        Q02388, Q9Y215, P49747, Q14019, P00450, P16870, Q8TCG5, P17927,        Q9NS37, Q9UJA2, P02741, P02511, P53674, O95825, O75390, Q9Y600,        P04141, P09919, P0DML2, Q14406, Q6UVK1, Q01459, Q9GZU7, P16410,        P35222, P53634, P07339, P08311, Q14247, O60494, Q14999, Q86UP6,        P61073, P05108, P05093, P04798, P05177, P08686, P11509, P20813,        P33261, P11712, P10635, P05181, P08684, Q8N907, P09172, P43146,        P07585, P20711, Q16832, Q9NR30, O00571, Q86XP3, Q9NY93, O75398,        P35659, P17661, Q96SL1, O94907, P10515, P09622, P36957, P24855,        Q8NFT8, O00429, Q8N608, P27487, P42658, Q14195, Q9BPU6, P21728,        P14416, Q08554, Q02487, Q14574, Q02413, Q14126, P32926, Q86SJ6,        P15924, Q03001, Q9NRD8, Q05923, O75923, O95905, Q9NTX5, Q16610,        O43854, P25101, Q15075, P68104, O00418, O95967, P01133, P00533,        P20042, P38919, Q04637, P08246, Q12926, Q14576, P26378, P15502,        P19622, P06733, P09104, P22413, O43768, P11171, P16422, P07099,        P34913, P01588, P11678, P58107, P04626, Q96RT1, Q8IUD2, Q14264,        P10768, P03372, Q9Y603, Q92817, Q9Y3B2, Q01780, Q13868, Q9NQT5,        Q9NPD3, Q9NQT4, Q5RKV6, Q15024, Q96B26, Q06265, P15311, P00488,        P08709, P00451, P00740, P15090, Q14320, P48023, P49327, Q8TES7,        P22087, P35555, Q75N90, P09467, P12319, O75015, O75636, Q7L513,        P02675, P11362, P62942, Q9UIM3, P20930, Q14315, O75955, Q14254,        O43155, P35916, P02751, Q04609, P01225, Q12841, O95954, P02794,        P02792, P09958, P35637, P51114, Q9UM11, P35575, O95166, P60520,        Q9UBS5, O75899, Q99259, Q05329, Q13065, P22466, Q14376, P04406,        P41250, P01350, P15976, P50440, P02774, P01275, Q8N6F7, P23434,        P55107, P50395, P56159, Q9UJY5, P01241, P01286, Q9UBU3, P09681,        O14908, P29033, Q9NS71, Q6ZMI3, P23415, P15104, Q61B77, P49915,        Q13823, P01148, P30968, Q92805, Q08379, Q08378, Q13439, A6NI86,        A8MQT2, Q14789, P07359, P55259, P40197, Q9HCN6, P14770, Q9NQX3,        P06744, Q13098, P24298, P18283, P42261, P42262, P42263, P48058,        O43424, P39086, Q13002, Q16478, Q05586, Q12879, Q13224, Q4V328,        Q13255, P41594, P28799, P07492, P08263, P21266, P78417, P09211,        Q00403, P35269, P25092, P08236, P02724, P07305, P16104, O75367,        P84243, P12081, Q96D42, P68871, Q13547, Q92769, O15379, P56524,        Q9UQL6, P19113, Q9UBI9, P51858, Q00341, Q9NRV9, O00291, O75146,        P54198, P16402, P58876, P62805, P19367, P09429, P26583, P04035,        Q01581, P54868, P05114, P05204, Q14541, P09651, P22626, Q99729,        Q14103, P52597, P31943, P31942, P61978, P14866, Q8WVV9, Q9NSC5,        Q99714, Q7Z5P4, P14060, P08238, P14625, P0DMV8, P0DMV9, P34932,        P11021, P11142, P04792, Q12988, P10809, Q92598, P08908, Q13639,        Q9Y4L1, P10997, Q05084, Q9UMF0, 075874, Q5TF58, Q16666, Q9BYX4,        P01563, P01574, P01579, Q9NWB7, P05019, P08069, P01344, Q9NZI8,        Q9Y6M1, O00425, P11717, P18065, P17936, P01876, P01877, P01854,        P01857, P01859, P01860, P01861, A6NGN9, Q8N6C5, P22301, Q13651,        Q08334, Q14005, Q16552, Q96PD4, Q14116, P01583, P01584, P14778,        P60568, Q9GZX6, P08700, P05112, P05231, P40189, Q96LU5, Q9NV31,        P29218, O14732, P12268, Q9NQS7, P01308, Q96T92, P06213, P46940,        Q14653, Q13568, P35568, P17301, P08514, P23229, P20701, P11215,        P05107, P05106, P16144, Q14643, Q9Y6Y0, 060674, P17275, Q15046,        P16389, P22459, Q9UK17, Q9NZI2, Q9NS61, P78508, P48050, P51787,        O43525, Q8N513, Q6PI47, P35968, Q9Y4F3, Q96Q89, P43626, P43628,        Q5JT82, Q53G59, Q8IXQ5, Q9UKR3, P03952, P26715, P26717, Q13241,        P13645, P02533, P19012, P08779, Q04695, P05783, P08727, P12035,        Q8N1N4, P05787, Q9NSB2, O15230, P11047, P13473, Q14739, P31025,        P13796, P07195, P01130, Q9Y2U8, P09382, P05162, P17931, Q08380,        Q3ZCW2, O95970, Q5TDP6, P22888, P49917, P07098, P02545, P20700,        Q03252, P61968, P29536, P08519, Q07954, P98164, O75096, Q8TF66,        Q32MZ4, Q8ND56, Q9Y4ZO, P02788, Q17RY6, P20645, Q8NHW3, P20916,        P43358, O15479, O60732, Q9H0U3, P46821, P11137, Q16584, O43318,        P45984, Q16644, P21941, O00339, P56270, P02144, Q9UIS9, P11226,        P02686, Q01726, P32245, Q8IVS2, Q99705, Q969V1, Q8TDD5, Q8NE86,        P40925, Q00987, O00255, P50579, P46013, Q16655, P03956, P45452,        P08253, P09237, P14780, Q13201, Q13875, Q16653, Q13724, Q14149,        Q9UBU8, O00566, Q99547, P40238, P05164, Q00013, Q9NZW5, P25189,        P22897, Q9Y605, P82909, P43246, P52701, Q13421, P26038, Q9UJ68,        P26927, Q13043, Q04912, Q9NZJ7, Q86UE4, P15941, Q8WX17, O15146,        Q9UIF7, P10242, P01106, Q99417, P12524, Q8N699, P12882, P35580,        P35749, Q9UKX3, Q7Z406, Q9Y2K3, Q9UKX2, P11055, Q9Y623, P13533,        P12883, A7E2Y1, P13535, P35579, B0I1T2, P54296, Q14CX7, E9PAV3,        Q13765, Q8WY41, Q96159, Q9UBB6, Q9UHB4, Q00604, P28331, P20929,        P07196, P07197, Q8NG66, Q8TD19, O60524, O94856, P01138, Q8N4C6,        P30414, P59047, Q8N427, Q13253, Q15155, P29475, P51513, Q9UNW9,        P55786, O60500, P06748, P01160, P17342, P01303, Q9Y5X4, Q8IXM6,        Q9ULB1, Q9HDB5, Q9Y4CO, Q9NXX6, P04629, Q16620, Q16288, Q02818,        P80303, Q14980, P49790, Q8TEM1, O15504, Q14990, Q5BJF6, Q9ULJ1,        Q6UX06, P78380, P41143, P35372, Q9P0S3, Q92791, Q9UQ80, Q13310,        Q9UM07, Q7Z2X7, Q5JRK9, Q96GU1, Q13177, Q99497, P09874, P40424,        Q15154, P12004, P29120, Q8WUM4, O95263, O76083, P16234, P09619,        O00330, P30101, Q8N165, O00151, Q5T2W1, P16284, P02776, P10720,        P35080, P18669, P00558, O95394, P35232, Q99623, Q9BVI0, Q92576,        O43175, P11309, O75364, Q9Y446, P04054, Q13018, P16885, Q15149,        Q9H7P9, P40967, P29590, Q01453, Q9NR77, P54277, P16233, P54317,        Q8ND90, Q9UL42, P00491, Q9H9Y6, O14802, Q99575, P16435, Q15063,        Q01851, Q12837, Q15181, P62937, O60437, P35813, P01298, Q9HAZ2,        P32119, Q13162, P30041, P13727, Q92954, P17612, P17252, P01236,        P04553, P04554, O60678, P04070, Q9UNN8, P54821, Q99811, P07477,        P24158, Q9BXM0, 043653, O75475, P20618, P40306, P49721, P28074,        P28062, P28065, P61289, Q6PGN9, P26599, Q8WV60, P01270, P06454,        Q06124, Q9Y2R2, P08575, Q12913, Q16849, Q92932, Q86Y79, Q9UHX1,        P20472, Q9BRP8, P51153, Q9UI14, Q15276, P63244, Q92878, Q06609,        P04049, Q15311, Q9UKM9, Q14498, P38159, P10745, Q06330, P53805,        O95199, Q9P258, P35243, P46063, P05451, Q8IX06, P57771, P08100,        P12271, O60930, O00584, Q9ULK6, Q99942, Q9UBF6, P13489, O75116,        Q01973, P15927, Q9Y2JO, Q9UNE2, Q02878, P05388, P05386, P05387,        Q9BUL9, P78346, P78345, P62277, P60866, O75676, O43159, Q15404,        O00442, Q92541, Q9NQC3, Q9Y265, Q9Y230, P48443, P21817, Q92736,        P31151, P04271, P0DJI8, P0DJI9, P10523, P49591, O43290, Q99590,        Q8WTV0, Q14108, P13521, P05408, Q14524, Q9BWW7, P34741, Q86SQ7,        Q9UDX4, Q13228, P16109, P04279, Q9HC62, P49908, Q9HD40, P01009,        P05543, P30740, P29508, P48594, P35237, P05121, P07093, P05155,        Q9BYW2, Q7Z333, Q8N474, Q9BWM7, Q99961, O15266, O60902, Q9NYZ4,        Q9Y336, Q9H0K1, Q14190, Q13239, Q14493, Q9H0C2, P12235, P05141,        Q9H2B4, O43511, P11168, Q8IWU4, O00400, P08195, Q8IWA5, P48751,        Q9Y6R1, Q9BRV3, Q92911, P37840, O76070, P08621, P09012, P14678,        P09234, P62314, P62316, P62318, P62304, P62306, P62308, P63162,        O14512, P00441, P04179, Q9BQB4, O00570, P56693, P35716, O15370,        O60248, Q9UN79, O95416, Q9H6I2, P35713, P48431, Q9Y651, P41225,        O94993, Q06945, P35711, P35712, Q9BT81, P57073, P48436, P08047,        P23497, Q13342, Q9H930, Q15506, Q8N0X2, P00995, P16150, O43791,        P10451, Q8TCT8, Q8TCT7, Q8TCT6, Q13813, Q13501, P10124, P61011,        O76094, Q05066, P05455, O43805, P61278, Q13586, Q9P246, P31948,        P49842, P16949, Q7Z7C7, Q13033, O75558, P61266, Q13190, Q8IWZ8,        Q9Y2ZO, Q8IWU6, P63165, P61956, P17600, P08247, P21579, P37837,        Q15633, Q13148, P26639, Q9NYW0, P20226, O60806, P24557, P17987,        O60522, O14746, P02787, P05549, Q92734, P10646, P02786, P01266,        P01137, P21980, Q08188, P49221, P07204, P40225, P10827, P10828,        Q9UPZ6, P31483, P29401, Q9Y490, O60602, Q8TDI7, P17152, P42167,        P42166, P01375, O00300, P43489, P19237, P48788, P19429, P13805,        P45379, P45378, P09430, Q8NDV7, P11387, Q969P6, P11388, Q13472,        O95985, P04637, Q9H3D4, O15350, P60174, P09493, P07202, P12270,        P56180, O43280, Q92519, Q96RU7, P19474, O15164, Q9UPN9, Q6AZZ1,        P10155, P48995, Q13507, Q7Z4N2, Q7Z2W7, Q9HBA0, Q9BZW7, P01222,        P16473, Q9H2G4, Q14166, Q8WZ42, P02766, P07437, O00294, Q15672,        Q9P2K2, Q86VQ3, Q6A555, P14679, Q9BZF9, Q13404, Q14139, O95155,        P11441, Q9UMX0, P17480, P09936, P15374, Q9Y3C8, P19224, P16662,        P07911, Q8TCY9, Q9Y6N9, Q13107, P63027, Q15836, P18206, P55072,        P21796, P08670, P04275, O75083, Q14191, P98170, Q13426, P13010,        P12956, P67809, Q9Y2T7, O43829, Q13105, Q15915, O95409, Q8N9L1,        Q9UDV7, Q9Y3S2, Q9UL40, Q14966, Q9H0M5, Q9Y5V0, Q96C28, Q9H5H4,        A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882,        P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40,        Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1, Q1HVF7, P03211,        Q13585, P04233, O15523, O14602, Q30201, P01891, P01892, P04439,        P05534, P10314, P10316, P13746, P16188, P16189, P16190, P18462,        P30443, P30447, P30450, P30453, P30455, P30456, P30457, P30459,        P30512, Q09160, P01889, P03989, P10319, P18463, P18464, P18465,        P30460, P30461, P30462, P30464, P30466, P30475, P30479, P30480,        P30481, P30483, P30484, P30485, P30486, P30487, P30488, P30490,        P30491, P30492, P30493, P30495, P30498, P30685, Q04826, Q29718,        Q29836, Q29940, Q31610, Q31612, Q95365, P04222, P10321, P30499,        P30501, P30504, P30505, P30508, P30510, Q07000, Q29865, Q29960,        Q29963, Q95604, Q9TNN7, P28067, P28068, P06340, P13765, P20036,        P04440, P01909, P01906, P01920, P05538, P01903, P01911, P01912,        P04229, P13760, P13761, P20039, Q29974, Q30134, Q30167, Q5Y7A7,        Q951E3, Q9GIY3, Q9TQE0, P79483, P13762, Q30154, P13747, P30511,        P17693, Q9BY66, Q29983, Q29980, P22090, Q03519, O14607, P08048;        in particular wherein the sequence fragment comprises or        consists of the AAV-8 capsid protein sequence LQQQNT (SEQ ID NO:        18), TTTGQNNNS (SEQ ID NO: 19) or GTANTQ (SEQ ID NO: 20);        optionally wherein the sequence fragment comprises at most five,        preferably at most four, more preferably at most three, even        more preferably at most two, especially at most one amino acid        substitutions.        Embodiment 27. The compound of any one of embodiments 1 to 26,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(a) is        identical to a sequence fragment of a protein, wherein the        protein is identified by one of the UniProt accession codes        listed in embodiment 26;        optionally wherein said sequence fragment comprises at most        five, preferably at most four, more preferably at most three,        even more preferably at most two, especially at most one amino        acid substitutions.        Embodiment 28. The compound of any one of embodiments 1 to 27,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(b) is        identical to a sequence fragment of a protein, wherein the        protein is identified by one of the UniProt accession codes        listed in embodiment 26;        optionally wherein said sequence fragment comprises at most        five, preferably at most four, more preferably at most three,        even more preferably at most two, especially at most one amino        acid substitutions.        Embodiment 29. The compound of any one of embodiments 1 to 28,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(a) is        identical to a sequence fragment of a protein and the entire        sequence,        optionally with the exception of an N-terminal and/or C-terminal        cysteine, of peptide P_(b) is identical to the same or another,        preferably another, sequence fragment of the same protein,        wherein the protein is identified by one of the UniProt        accession codes listed in embodiment 26;        optionally wherein said sequence fragment and/or said another        sequence fragment comprises at most five, preferably at most        four, more preferably at most three, even more preferably at        most two, especially at most one amino acid substitutions.        Embodiment 30. The compound of any one of embodiments 1 to 29,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of at least one        occurrence of P, preferably of at least 10% of all occurrences        of P, more preferably of at least 25% of all occurrences of P,        yet more preferably of at least 50% of all occurrences of P,        even more preferably of at least 75% of all occurrences of P,        yet even more preferably of at least 90% of all occurrences of P        or even of at least 95% of all occurrences of P, especially of        all of the occurrences of P, is identical to a sequence fragment        of an amino-acid sequence of Alpha-1-proteinase inhibitor,        Alglucerase, Taliglucerase alfa, Pegademase, Agalsidase beta,        Alglucosidase alfa, Laronidase, Idursulfase, Elosulfase alfa,        Galsulfase, Sebelipase alfa, Cerliponase alfa, Sebelipase alfa,        Asfotase Alfa, Elapegademase, Olipudase alpha, Velmanase alpha,        N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,        Pegloticase, Human Antithrombin III, Plasma protease C1        inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab,        Coagulation factor VIIa Recombinant Human, Antihemophilic factor        human recombinant, Von Willebrand Factor Human, Susoctocog alfa,        Antihemophilic factor human recombinant, Antihemophilic factor,        human recombinant, Oprelvekin, Aldesleukin, Rilonacept,        Anakinra, Denileukin diftitox, Erythropoietin, Interferon        beta-la, Interferon alfa, interferon alfa-2b, interferon        alfacon-1, interferon gamma-1b, interferon alfa-2b recombinant,        growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1        (UniProt P05019), PTH (UniProt P01270), Thyrotropin alfa,        Choriogonadotropin alfa, Follitropin, Lutropin alfa,        Somatotropin, Albiglutide, Metreleptin, Corifollitropin alfa,        Filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF        (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin,        GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaplermin,        Palifermin, Tasonermin, Aflibercept, Rilonacept, Romiplostim,        Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa, Rilonacept,        Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,        Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,        Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,        Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab        monatox, Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab,        Erenumab, Emicizumab or Atezolizumab;        optionally wherein said sequence fragment comprises at most        five, preferably at most four, more preferably at most three,        even more preferably at most two, especially at most one amino        acid substitutions.        Embodiment 31. The compound of any one of embodiments 1 to 30,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(a) is        identical to a sequence fragment of an amino-acid sequence of        Alpha-1-proteinase inhibitor, Alglucerase, Taliglucerase alfa,        Pegademase, Agalsidase beta, Alglucosidase alfa, Laronidase,        Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa,        Cerliponase alfa, Sebelipase alfa, Asfotase Alfa, Elapegademase,        Olipudase alpha, Velmanase alpha,        N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,        Pegloticase, Human Antithrombin III, Plasma protease C1        inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab,        Coagulation factor VIIa Recombinant Human, Antihemophilic factor        human recombinant, Von Willebrand Factor Human, Susoctocog alfa,        Antihemophilic factor human recombinant, Antihemophilic factor,        human recombinant, Oprelvekin, Aldesleukin, Rilonacept,        Anakinra, Denileukin diftitox, Erythropoietin, Interferon        beta-la, Interferon alfa, interferon alfa-2b, interferon        alfacon-1, interferon gamma-1b, interferon alfa-2b recombinant,        growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1        (UniProt P05019), PTH (UniProt P01270), Thyrotropin alfa,        Choriogonadotropin alfa, Follitropin, Lutropin alfa,        Somatotropin, Albiglutide, Metreleptin, Corifollitropin alfa,        Filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF        (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin,        GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaplermin,        Palifermin, Tasonermin, Aflibercept, Rilonacept, Romiplostim,        Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa, Rilonacept,        Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,        Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,        Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,        Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab        monatox, Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab,        Erenumab, Emicizumab or Atezolizumab;        optionally wherein said sequence fragment comprises at most        five, preferably at most four, more preferably at most three,        even more preferably at most two, especially at most one amino        acid substitutions.        Embodiment 32. The compound of any one of embodiments 1 to 31,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(b) is        identical to a sequence fragment of an amino-acid sequence of        Alpha-1-proteinase inhibitor, Alglucerase, Taliglucerase alfa,        Pegademase, Agalsidase beta, Alglucosidase alfa, Laronidase,        Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa,        Cerliponase alfa, Sebelipase alfa, Asfotase Alfa, Elapegademase,        Olipudase alpha, Velmanase alpha,        N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,        Pegloticase, Human Antithrombin III, Plasma protease C1        inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab,        Coagulation factor VIIa Recombinant Human, Antihemophilic factor        human recombinant, Von Willebrand Factor Human, Susoctocog alfa,        Antihemophilic factor human recombinant, Antihemophilic factor,        human recombinant, Oprelvekin, Aldesleukin, Rilonacept,        Anakinra, Denileukin diftitox, Erythropoietin, Interferon        beta-la, Interferon alfa, interferon alfa-2b, interferon        alfacon-1, interferon gamma-1b, interferon alfa-2b recombinant,        growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1        (UniProt P05019), PTH (UniProt P01270), Thyrotropin alfa,        Choriogonadotropin alfa, Follitropin, Lutropin alfa,        Somatotropin, Albiglutide, Metreleptin, Corifollitropin alfa,        Filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF        (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin,        GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaplermin,        Palifermin, Tasonermin, Aflibercept, Rilonacept, Romiplostim,        Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa, Rilonacept,        Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,        Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,        Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,        Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab        monatox, Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab,        Erenumab, Emicizumab or Atezolizumab;        optionally wherein said sequence fragment comprises at most        five, preferably at most four, more preferably at most three,        even more preferably at most two, especially at most one amino        acid substitutions.        Embodiment 33. The compound of any one of embodiments 1 to 32,        wherein the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(a) is        identical to a sequence fragment of an amino-acid sequence and        the entire sequence, optionally with the exception of an        N-terminal and/or C-terminal cysteine, of peptide P_(b) is        identical to the same or another, preferably another, sequence        fragment of the same amino-acid sequence, wherein the amino-acid        sequence is an amino-acid sequence of Alpha-1-proteinase        inhibitor, Alglucerase, Taliglucerase alfa, Pegademase,        Agalsidase beta, Alglucosidase alfa, Laronidase, Idursulfase,        Elosulfase alfa, Galsulfase, Sebelipase alfa, Cerliponase alfa,        Sebelipase alfa, Asfotase Alfa, Elapegademase, Olipudase alpha,        Velmanase alpha,        N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,        Pegloticase, Human Antithrombin III, Plasma protease C1        inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab,        Coagulation factor VIIa Recombinant Human, Antihemophilic factor        human recombinant, Von Willebrand Factor Human, Susoctocog alfa,        Antihemophilic factor human recombinant, Antihemophilic factor,        human recombinant, Oprelvekin, Aldesleukin, Rilonacept,        Anakinra, Denileukin diftitox, Erythropoietin, Interferon        beta-la, Interferon alfa, interferon alfa-2b, interferon        alfacon-1, interferon gamma-1b, interferon alfa-2b recombinant,        growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1        (UniProt P05019), PTH (UniProt P01270), Thyrotropin alfa,        Choriogonadotropin alfa, Follitropin, Lutropin alfa,        Somatotropin, Albiglutide, Metreleptin, Corifollitropin alfa,        Filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF        (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin,        GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaplermin,        Palifermin, Tasonermin, Aflibercept, Rilonacept, Romiplostim,        Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa, Rilonacept,        Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,        Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,        Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,        Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab        monatox, Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab,        Erenumab, Emicizumab or Atezolizumab;        optionally wherein said sequence fragment and/or said another        sequence fragment comprises at most five, preferably at most        four, more preferably at most three, even more preferably at        most two, especially at most one amino acid substitutions.        Embodiment 34. The compound of any one of embodiments 1 to 33,        wherein each of the peptide n-mers is covalently bound to the        biopolymer scaffold, preferably via a linker each.        Embodiment 35. The compound of any one of embodiments 1 to 34,        wherein at least one of said linkers is selected from disulphide        bridges and PEG molecules.        Embodiment 36. The compound of any one of embodiments 1 to 35,        wherein at least one of the spacers S is selected from PEG        molecules or glycans.        Embodiment 37. The compound of any one of embodiments 1 to 36,        wherein at least one occurrence of P is P_(a) and at least one        occurrence of P is P_(b),

wherein P_(a) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein P_(b) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(a) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code P02708, O15146 or 075096, optionally wherein saidsequence fragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(b) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code P02708, O15146 or 075096, optionally wherein saidsequence fragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions.

Embodiment 38. The compound of any one of embodiments 14 to 37, wherein,in particular for P_(a) and/or P_(b), said sequence fragment of theprotein is a fragment of the sequence consisting of amino acids 21-255of the AChR subunit alpha sequence identified by UniProt accession codeP02708 (optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)).Embodiment 39. The compound of any one of embodiments 14 to 38, wherein,in particular for P_(a) and/or P_(b), said sequence fragment of theprotein is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO:1), preferably of the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK(SEQ ID NO: 3).Embodiment 40. The compound of any one of embodiments 6 to 39, whereinpeptide P_(a) and/or peptide P_(b) consist of the sequence VKKIHIPSEKG(SEQ ID NO: 4) optionally with an N-terminal and/or C-terminal cysteineresidue.Embodiment 41. The compound of any one of embodiments 6 to 40, whereinthe first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(b).Embodiment 42. The compound of any one of embodiments 6 to 40, whereinthe peptide P_(a) and the peptide P_(b) comprise the same amino-acidsequence fragment, wherein the amino-acid sequence fragment has a lengthof at least 5 amino acids, even more preferably at least 6 amino acids,yet even more preferably at least 7 amino acids, especially at least 8amino acids or even at least 9 amino acids.Embodiment 43. The compound of any one of embodiments 1 to 36, whereinat least one occurrence of P is P_(a) and at least one occurrence of Pis P_(b),

wherein P_(a) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein P_(b) is a peptide with a sequence length of 5-13, preferably7-13, amino acids,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(a) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code Q1HVF7, P03211, Q13585 or P30556, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions,

wherein the entire sequence, optionally with the exception of anN-terminal and/or C-terminal cysteine, of peptide P_(b) is identical toa sequence fragment of a protein, wherein the protein is identified byUniProt accession code Q1HVF7, P03211, Q13585 or P30556, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions.

Embodiment 44. The compound of any one of embodiments 14 to 36 and 43,wherein, in particular for P_(a) and/or P_(b), said sequence fragment ofthe protein is a fragment of the sequence RPQKRPSCIGCKGTH (SEQ ID NO: 5)or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably of the sequence KRPSCIGCK(SEQ ID NO: 7).Embodiment 45. The compound of any one of embodiments 14 to 36 and 43 to44, wherein, in particular for P_(a) and/or P_(b), said sequencefragment of the protein is a fragment of any one of the sequencesMILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO:9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), DVLIQLGIIRDCR (SEQID NO: 11), more preferably of the sequence AFHYESQ (SEQ ID NO: 12).Embodiment 46. The compound of any one of embodiments 6 to 36 and 43 to45, wherein peptide P_(a) and/or peptide P_(b) consist of the sequenceGRPQKRPSCIG (SEQ ID NO: 13) optionally with an N-terminal and/orC-terminal cysteine residue.Embodiment 47. The compound of embodiments 6 to 36 and 43 to 46, whereinthe first peptide n-mer is P_(a)-S-P_(b) and the second peptide n-mer isP_(a)-S-P_(b).Embodiment 48. The compound of embodiments 6 to 36 and 43 to 47, whereinthe peptide P_(a) and the peptide P_(b) comprise the same amino-acidsequence fragment, wherein the amino-acid sequence fragment has a lengthof at least 5 amino acids, even more preferably at least 6 amino acids,yet even more preferably at least 7 amino acids, especially at least 8amino acids or even at least 9 amino acids.Embodiment 49. A compound, preferably for the sequestration (ordepletion) of anti human muscle nicotinic acetylcholine receptor (AChR)antibodies, anti human muscle-specific receptor tyrosine kinaseantibodies and/or anti human low-density lipoprotein receptor relatedprotein 4 antibodies present in a human individual, the compoundcomprising a biopolymer scaffold and at least two peptides with asequence length of 7-13 amino acids, wherein each of the peptidesindependently comprises a 7-13 amino-acid sequence fragment of the AChRsubunit alpha sequence identified by UniProt accession code P02708(optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)) or of the muscle-specificreceptor tyrosine kinase sequence identified by UniProt accession code015146 (optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)) or of the low-density lipoproteinreceptor related protein 4 sequence identified by UniProt accession code075096 (optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed)),wherein the peptides are covalently bound to the biopolymer scaffold,wherein the biopolymer scaffold is selected from the group consisting ofhuman globulins and human albumin.Embodiment 50. The compound of embodiment 49, wherein the at least twopeptides comprise a peptide P₁ and a peptide P₂, wherein P₁ and P₂comprise the same 7-13 amino-acid sequence fragment of AChR subunitalpha, wherein P₁ and P₂ are present in form of a peptide dimerP₁-S-P₂, wherein S is a non-peptide spacer, wherein the peptide dimer iscovalently bound to the biopolymer scaffold, preferably via a linker.Embodiment 51. The compound of 49 or 50, wherein said 7-13 amino-acidsequence fragment of AChR subunit alpha is a fragment of the sequenceconsisting of amino acids 21-255 of the AChR subunit alpha sequenceidentified by UniProt accession code P02708 (optionally wherein thesequence fragment comprises at most five, preferably at most four, morepreferably at most three, even more preferably at most two, especiallyat most one amino acid substitutions (e.g. such that a mimotope isformed)).Embodiment 52. The compound of any one of embodiments 49 to 51, whereinsaid 7-13 amino-acid sequence fragment of AChR subunit alpha is afragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferablyof the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3);optionally wherein the sequence fragment comprises at most five,preferably at most four, more preferably at most three, even morepreferably at most two, especially at most one amino acid substitutions(e.g. such that a mimotope is formed).Embodiment 53. The compound of any one of embodiments 49 to 52, whereinthe peptides have a sequence length of 8-13 amino acids, preferably 9-12amino acids, more preferably 10-12 amino acids, especially wherein thepeptides consist of the sequence VKKIHIPSEKG (SEQ ID NO: 4) optionallywith an N-terminal and/or C-terminal cysteine residue.Embodiment 54. The compound of any one of embodiments 1 to 53, whereinthe compound further comprises at least one peptide with a sequencelength of 7-13 amino acids, wherein the at least one peptide comprises a7-13 amino-acid sequence fragment of the muscle-specific receptortyrosine kinase sequence identified by UniProt accession code 015146 orof the low-density lipoprotein receptor related protein 4 sequenceidentified by UniProt accession code 075096, wherein the at least onepeptide is covalently bound to the biopolymer scaffold, preferably via alinker.Embodiment 55. A compound, preferably for the sequestration (ordepletion) of anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1)antibodies, anti human melatonin-related receptor (GPR50) antibodiesand/or anti human type-1 angiotensin II receptor (AT1AR) antibodiespresent in a human individual, the compound comprising a biopolymerscaffold and at least two peptides with a sequence length of 7-13 aminoacids,

wherein each of the peptides independently comprises a 7-13 amino-acidsequence fragment of the EBNA1 sequence identified by UniProt accessioncode Q1HVF7 or P03211 or of the GPR50 sequence identified by UniProtaccession code Q13585 or of the type-1 angiotensin II receptor (AT1AR)sequence identified by UniProt accession code P30556, wherein thepeptides are covalently bound to the biopolymer scaffold,

wherein the biopolymer scaffold is selected from the group consisting ofhuman globulins, preferably from the group consisting of humanimmunoglobulins and human haptoglobin, and human albumin.

Embodiment 56. The compound of embodiment 55, wherein the at least twopeptides comprise a peptide P₁ and a peptide P₂, wherein P₁ and P₂comprise the same 7-13 amino-acid sequence fragment of said EBNA1sequence or said GPR50 sequence, wherein P₁ and P₂ are present in formof a peptide dimer P₁-S-P₂, wherein S is a non-peptide spacer, whereinthe peptide dimer is covalently bound to the biopolymer scaffold,preferably via a linker.Embodiment 57. The compound of embodiment 55 or 56, wherein said 7-13amino-acid sequence fragment is a fragment of the sequenceRPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6),preferably of the sequence KRPSCIGCK (SEQ ID NO: 7); and/or wherein thepeptides have a sequence length of 8-13 amino acids, preferably 9-12amino acids, more preferably 10-12 amino acids, especially wherein atleast one of the at least two, preferably each of the peptides consistof the sequence GRPQKRPSCIG (SEQ ID NO: 13) optionally with anN-terminal and/or C-terminal cysteine residue.Embodiment 58. The compound of any one of embodiments 55 to 57, whereinsaid 7-13 amino-acid sequence fragment is a fragment of any one of thesequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK(SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10),DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably of the sequence AFHYESQ(SEQ ID NO: 12).Embodiment 59. The compound of any one of embodiments 1 to 58, whereinthe compound further comprises at least one peptide with a sequencelength of 7-13 amino acids, wherein the at least one peptide comprises a7-13 amino-acid sequence fragment of the type-1 angiotensin II receptor(AT1AR) sequence identified by UniProt accession code P30556, preferablyof any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8),TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ IDNO: 10), DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably of the sequenceAFHYESQ (SEQ ID NO: 12); wherein the at least one peptide is covalentlybound to the biopolymer scaffold, preferably via a linker.Embodiment 60. The compound of any one of embodiments 1 to 59, whereineach of the peptides is covalently bound to the scaffold via a linker.Embodiment 61. The compound of any one embodiments 1 to 60, wherein thebiopolymer scaffold is selected from human immunoglobulins and humanhaptoglobins.Embodiment 62. The compound of embodiment any one of embodiments 1 to61, wherein the biopolymer scaffold is human haptoglobin.Embodiment 63. The compound of any one of embodiments 49 to 62, whereinat least one of the at least two peptides is circularized.Embodiment 64. The compound of any one of embodiments 1 to 63, whereinthe compound is non-immunogenic in humans.Embodiment 65. A pharmaceutical composition comprising the compound ofany one of embodiments 1 to 64 and at least one pharmaceuticallyacceptable excipient.Embodiment 66. The pharmaceutical composition of embodiment 65, whereinthe composition is prepared for intraperitoneal, subcutaneous,intramuscular and/or intravenous administration and/or wherein thecomposition is for repeated administration.Embodiment 67. The pharmaceutical composition of any one of embodiments1 to 66, wherein the molar ratio of peptide P to biopolymer scaffold inthe composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, morepreferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, yeteven more preferably from 6:1 to 60:1, especially from 7:1 to 50:1 oreven from 8:10 to 40:1.Embodiment 68. The pharmaceutical composition of any one of embodiments6 to 67, wherein the molar ratio of peptide P_(a) to biopolymer scaffoldin the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1,more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1,yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1or even from 8:10 to 40:1.Embodiment 69. The pharmaceutical composition of any one of embodiments6 to 68, wherein the molar ratio of peptide P_(b) to biopolymer scaffoldin the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1,more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1,yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1or even from 8:10 to 40:1.Embodiment 70. The pharmaceutical composition of any one of embodiments65 to 69 for use in therapy.Embodiment 71. The pharmaceutical composition for use according toembodiment 70, for use in prevention or treatment of an autoimmunedisease in an individual having the autoimmune disease or being at riskof developing the autoimmune disease.Embodiment 72. The pharmaceutical composition for use according toembodiment 71, wherein the autoimmune disease is selected from the groupconsisting of neuromyelitis optica, seropositive neuromyelitis opticaspectrum disorders, autoimmune-encephalitis, multiple sclerosis,amyotrophic lateral sclerosis, systemic lupus erythematosus dementia,myasthenia gravis, in particular transient neonatal myasthenia gravis,dilatative Cardiomyopathy, pulmonary hypertension, Sjögren's Syndrome,celiac Disease, Graves Disease, Goodpasture Disease, preeclampsia,Behcet's Disease, systemic sclerosis, hypertension, type I diabetes,type II diabetes, systemic lupus erythematosus, antiN-methyl-D-aspartate receptor (NMDAR) encephalitis, antiphospholipidsyndrome, membranous nephropathy, primary biliary cholangitis,amyotrophic lateral sclerosis, Chagas disease cardiomyopathy, immunethrombocytopenic purpura, pemphigus vulgaris, bullous pemphigoid,epidermolysis bullosa acquisita and bullous systemic lupuserythematosus.Embodiment 73. The pharmaceutical composition for use according toembodiment 70, for use in prevention or treatment of transplantrejection in an individual having a transplant or eligible for atransplantation.Embodiment 74. The pharmaceutical composition for use according toembodiment 70, for use in prevention or treatment of adverse reactionsbased on anti-drug antibodies or anti-gene-delivery vector antibodies,such as anti-AAV antibodies, in an individual undergoing therapy withthe drug or eligible for therapy with the drug, or in an individualundergoing gene therapy or eligible for gene therapy,preferably wherein the drug is a peptide or protein, especially selectedfrom the group of enzymes, enzyme inhibitors, antibodies, antibodyfragments, antibody mimetics, antibody-drug conjugates, hormones, growthfactors, clotting factors and cytokines, preferably wherein the entiresequence, optionally with the exception of an N-terminal and/orC-terminal cysteine, of at least one occurrence of peptide P, or ofpeptide P_(a) and/or of peptide P_(b) is identical to a sequencefragment of an amino-acid sequence of the peptide or protein, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions.Embodiment 75. The pharmaceutical composition for use according toembodiment 74, wherein the drug is Alpha-1-proteinase inhibitor,Alglucerase, Taliglucerase alfa, Pegademase, Agalsidase beta,Alglucosidase alfa, Laronidase, Idursulfase, Elosulfase alfa,Galsulfase, Sebelipase alfa, Cerliponase alfa, Sebelipase alfa, AsfotaseAlfa, Elapegademase, Olipudase alpha, Velmanase alpha,N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,Pegloticase, Human Antithrombin III, Plasma protease C1 inhibitor,Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulation factor VIIaRecombinant Human, Antihemophilic factor human recombinant, VonWillebrand Factor Human, Susoctocog alfa, Antihemophilic factor humanrecombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab,preferably wherein the entire sequence, optionally with the exception ofan N-terminal and/or C-terminal cysteine, of at least one occurrence ofpeptide P, or of peptide P_(a) and/or of peptide P_(b) is identical to asequence fragment of an amino-acid sequence of the drug, optionallywherein said sequence fragment comprises at most five, preferably atmost four, more preferably at most three, even more preferably at mosttwo, especially at most one amino acid substitutions.Embodiment 76. The pharmaceutical composition for use according to anyone of embodiments 70 to 75, wherein one or more antibodies are presentin the individual which are specific for at least one occurrence ofpeptide P, or for peptide P_(a) and/or peptide P_(b), preferably whereinsaid antibodies are related to said disease.Embodiment 77. The pharmaceutical composition for use according to anyone of embodiments 70 to 76, wherein the composition is non-immunogenicin the individual.Embodiment 78. The pharmaceutical composition for use according to anyone of embodiments 70 to 77, wherein the composition is administered ata dose of 1-1000 mg, preferably 2-500 mg, more preferably 3-250 mg, evenmore preferably 4-100 mg, especially 5-50 mg, compound per kg bodyweight of the individual.Embodiment 79. The pharmaceutical composition for use according to anyone of embodiments 70 to 78, wherein the composition is administeredintraperitoneally, subcutaneously, intramuscularly or intravenously.Embodiment 80. A method of sequestering (or depleting) one or moreantibodies present in an individual, comprising

obtaining a pharmaceutical composition as defined in any one ofembodiments 65 to 69, wherein the composition is non-immunogenic in theindividual and wherein the one or more antibodies present in theindividual are specific for at least one occurrence of P, or for peptideP_(a) and/or peptide P_(b); and

administering the pharmaceutical composition to the individual.

Embodiment 81. The method of embodiment 80, wherein the individual is anon-human animal, preferably a non-human primate, a sheep, a pig, a dogor a rodent, in particular a mouse.Embodiment 82. The method of embodiments 80 or 81, wherein thebiopolymer scaffold is autologous with respect to the individual,preferably wherein the biopolymer scaffold is an autologous protein.Embodiment 83. The method of any one of embodiments 80 to 82, whereinthe individual is administered a heterologous protein, preferably aheterologous antibody such as a nanobody, and wherein the one or moreantibodies present in the individual are specific for said heterologousprotein, preferably wherein said administering of the heterologousprotein is prior to, concurrent with and/or subsequent to saidadministering of the pharmaceutical composition.Embodiment 84. The method of any one of embodiments 80 to 83, whereinthe individual is a non-human animal and the heterologous protein ishuman or humanized.Embodiment 85. The method of any one of embodiments 80 to 82, whereinthe individual is administered a drug and wherein the one or moreantibodies present in the individual are specific for said drug,preferably wherein said administering of the drug is prior to,concurrent with and/or subsequent to said administering of thepharmaceutical composition.Embodiment 86. The method of embodiment 85, wherein the drug isAlpha-1-proteinase inhibitor, Alglucerase, Taliglucerase alfa,Pegademase, Agalsidase beta, Alglucosidase alfa, Laronidase,Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa, Cerliponasealfa, Sebelipase alfa, Asfotase Alfa, Elapegademase, Olipudase alpha,Velmanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase,Rasburicase, Pegloticase, Human Antithrombin III, Plasma protease C1inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulationfactor VIIa Recombinant Human, Antihemophilic factor human recombinant,Von Willebrand Factor Human, Susoctocog alfa, Antihemophilic factorhuman recombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab.Embodiment 87. The method of any one of embodiments 80 to 86, whereinthe individual is healthy.Embodiment 88. The method of any one of embodiments 80 to 87, whereinthe composition is administered intraperitoneally, subcutaneously,intramuscularly or intravenously.Embodiment 89. A pharmaceutical composition, comprising the compound ofany one of embodiments 1 to 64 and further comprising an active agentsuch as a protein or a peptide and optionally at least onepharmaceutically acceptable excipient,wherein the active agent comprises a peptide fragment with a sequencelength of 2-13 amino acids, preferably 3-11 amino acids, more preferably4-9 amino acids, especially 5-8 amino acids, andwherein the sequence of at least one occurrence of peptide P, or peptideP_(a) and/or peptide P_(b), of the compound is at least 70% identical,preferably at least 75% identical, more preferably at least 80%identical, yet more preferably at least 85% identical, even morepreferably at least 90% identical, yet even more preferably at least 95%identical, especially completely identical to the sequence of saidpeptide fragment.Embodiment 90. The pharmaceutical composition of embodiment 89, whereinthe active agent is an enzyme, preferably a human enzyme, an antibody,preferably a human or humanized antibody, a hormone, a growth factor, aclotting factor, a cytokine or a gene delivery vector, such as AAV.Embodiment 91. The pharmaceutical composition of embodiment 89 or 90,wherein the active agent is Alpha-1-proteinase inhibitor, Alglucerase,Taliglucerase alfa, Pegademase, Agalsidase beta, Alglucosidase alfa,Laronidase, Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa,Cerliponase alfa, Sebelipase alfa, Asfotase Alfa, Elapegademase,Olipudase alpha, Velmanase alpha,N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, Rasburicase,Pegloticase, Human Antithrombin III, Plasma protease C1 inhibitor,Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulation factor VIIaRecombinant Human, Antihemophilic factor human recombinant, VonWillebrand Factor Human, Susoctocog alfa, Antihemophilic factor humanrecombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab.Embodiment 92. The pharmaceutical composition of any one of embodiments89 to 91, wherein the composition is prepared for intravenousadministration.Embodiment 93. The pharmaceutical composition of any one of embodiments89 to 92, wherein the composition is an aqueous solution.Embodiment 94. The pharmaceutical composition of any one of embodiments89 to 93 for use in inhibition of an immune reaction, preferably anantibody-mediated immune reaction, against the active agent.Embodiment 95. The pharmaceutical composition for use according toembodiment 94, wherein the composition is non-immunogenic in theindividual.Embodiment 96. A method of inhibiting an immune reaction to a treatmentwith an active agent in an individual in need of treatment with theactive agent, comprising

obtaining a pharmaceutical composition as defined in any one ofembodiments 89 to 95; wherein the compound of the pharmaceuticalcomposition is non-immunogenic in the individual, and

administering the pharmaceutical composition to the individual.

Embodiment 97. The method of embodiment 96, wherein the individual ishuman.Embodiment 98. The method of embodiment 96 or 97, wherein the biopolymerscaffold is autologous with respect to the individual, preferablywherein the biopolymer scaffold is an autologous protein.Embodiment 99. The method of any one of embodiments 96 to 98, whereinthe composition is administered intraperitoneally, subcutaneously,intramuscularly or intravenously.Embodiment 100. A method of providing a compound according to any one ofembodiments 1 to 64, comprising the steps of

identifying at least one individual having an undesired antibody againstan antigen,

screening a peptide library to identify a peptide mimotope for which theundesired antibody is specific, and

providing the compound, wherein at least one occurrence of P of thecompound comprises the entire sequence of the peptide mimotope.

Embodiment 101. The method of embodiment 100, wherein the antigen is apeptide or protein, wherein the sequence of the peptide or protein doesnot comprise the entire sequence of the peptide mimotope.Embodiment 102. The method of embodiment 100 or 101, wherein at least10% of all occurrences of P comprise the entire sequence of the peptidemimotope, more preferably wherein at least 25% of all occurrences of Pcomprise the entire sequence of the peptide mimotope, yet morepreferably wherein at least 50% of all occurrences of P comprise theentire sequence of the peptide mimotope, even more preferably wherein atleast 75% of all occurrences of P comprise the entire sequence of thepeptide mimotope, yet even more preferably wherein at least 90% of alloccurrences of P comprise the entire sequence of the peptide mimotope oreven wherein at least 95% of all occurrences of P comprise the entiresequence of the peptide mimotope, especially wherein all of theoccurrences of P comprise the entire sequence of the peptide mimotope.Embodiment 103. The method of any one of embodiments 100 to 102, whereinthe peptide library comprises circular peptides.Embodiment 104. The method of any one of embodiments 100 to 103, whereinthe peptide library is a phage display library, a peptide microarraylibrary or a soluble peptide library.Embodiment 105. The method of any one of embodiments 100 to 104, whereinthe screening of the peptide library is performed with a serum obtainedfrom the at least one individual, wherein the serum comprises theundesired antibody.Embodiment 106. The method of any one of embodiments 100 to 105, whereinthe compound is non-immunogenic in the at least one individual.Embodiment 107. The method of any one of embodiments 100 to 106, whereinthe at least one individual is a non-human animal, preferably anon-human primate, a sheep, a pig, a dog or a rodent, in particular amouse.Embodiment 108. The method of any one of embodiments 100 to 106, whereinthe at least one individual is human.Embodiment 109. The method of any one of embodiments 100 to 108, whereinthe biopolymer scaffold is autologous with respect to the at least oneindividual, preferably wherein the biopolymer scaffold is an autologousprotein.Embodiment 110. The method of any one of embodiments 100 to 109, whereinthe at least one individual has been administered a heterologousprotein, preferably a heterologous antibody such as a nanobody, andwherein the antigen is said heterologous protein.Embodiment 111. The method of any one of embodiments 100 to 110, whereinthe at least one individual is a non-human animal and the heterologousprotein is human or humanized.Embodiment 112. The method of any one of embodiments 100 to 111, whereinthe individual has been administered a drug and wherein the drug is theantigen.Embodiment 113. The method of embodiment 112, wherein the drug is anenzyme, preferably a human enzyme, an antibody, preferably a human orhumanized antibody, a hormone, a growth factor, a clotting factor, acytokine or a gene delivery vector, such as AAV.Embodiment 114. The method of embodiment 112, wherein the drug isAlpha-1-proteinase inhibitor, Alglucerase, Taliglucerase alfa,Pegademase, Agalsidase beta, Alglucosidase alfa, Laronidase,Idursulfase, Elosulfase alfa, Galsulfase, Sebelipase alfa, Cerliponasealfa, Sebelipase alfa, Asfotase Alfa, Elapegademase, Olipudase alpha,Velmanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase,Rasburicase, Pegloticase, Human Antithrombin III, Plasma protease C1inhibitor, Turoctocog alfa, Drotrecogin alfa, Emicizumab, Coagulationfactor VIIa Recombinant Human, Antihemophilic factor human recombinant,Von Willebrand Factor Human, Susoctocog alfa, Antihemophilic factorhuman recombinant, Antihemophilic factor, human recombinant, Oprelvekin,Aldesleukin, Rilonacept, Anakinra, Denileukin diftitox, Erythropoietin,Interferon beta-la, Interferon alfa, interferon alfa-2b, interferonalfacon-1, interferon gamma-1b, interferon alfa-2b recombinant, growthhormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProtP05019), PTH (UniProt P01270), Thyrotropin alfa, Choriogonadotropinalfa, Follitropin, Lutropin alfa, Somatotropin, Albiglutide,Metreleptin, Corifollitropin alfa, Filgrastim, FGF2 (UniProt P09038),NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560),Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344),Becaplermin, Palifermin, Tasonermin, Aflibercept, Rilonacept,Romiplostim, Tagraxofusp, Efmoroctocog alfa, Eftrenonacog alfa,Rilonacept, Belatacept, Atacicept, Albutrepenonacog alfa, Dulaglutide,Etanercept, Asfotase Alfa, Natalizumab, Rituximab, Adalimumab,Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab,Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab monatox,Ibritumomab tiuxetan, Abciximab, Rituximab, Ofatumumab, Erenumab,Emicizumab or Atezolizumab.Embodiment 115. The method of any one of embodiments 100 to 114, whereinthe individual is healthy.Embodiment 116. The method of any one of embodiments 100 to 115, whereinthe undesired antibody is an autoantibody of the at least oneindividual.

The present invention is further illustrated by the following figuresand examples, without being restricted thereto.

In the context of the following figures and examples the compound of thepresent invention is also referred to as “Selective Antibody DepletionCompound” (SADC).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: The compound of the present invention successfully reduces thetitre of undesired antibodies. Each compound of the invention wasapplied at time point 0 by i.p. injection into Balb/c mice pre-immunizedby peptide immunization against a defined antigen. Each top panel showsanti-peptide titers (0.5× dilution steps; X-axis shows log(X) dilutions)against OD values (y-axis) according to a standard ELISA detecting thecorresponding antibody. Each bottom panel shows titers Log IC50 (y-axis)before injection of each compound of the invention (i.e. titers at −48 hand −24 h) and after application of each compound of the invention (i.e.titers+24 h, +48 h and +72 h after injection; indicated on the x-axis).(A) Compound with albumin as the biopolymer scaffold that binds toantibodies directed against EBNA1 (associated with pre-eclampsia). Themice were pre-immunized with a peptide vaccine carrying the EBNA-1 modelepitope. (B) Compound with albumin as the biopolymer scaffold that bindsto antibodies directed against a peptide derived from the human AChRprotein MIR (associated with myasthenia gravis). The mice werepre-immunized with a peptide vaccine carrying the AChR MIR modelepitope. (C) Compound with immunoglobulin as the biopolymer scaffoldthat binds to antibodies directed against EBNA1 (associated withpre-eclampsia). The mice were pre-immunized with a peptide vaccinecarrying the EBNA-1 model epitope. (D) Compound with haptoglobin as thebiopolymer scaffold that binds to antibodies directed against EBNA1(associated with pre-eclampsia). The mice were pre-immunized with apeptide vaccine carrying the EBNA-1 model epitope. (E) Demonstration ofselectivity using the same immunoglobulin-based compound of theinvention binding to antibodies directed against EBNA1 that was used inthe experiment shown in panel C. The mice were pre-immunized with anunrelated amino acid sequence. No titre reduction occurred,demonstrating selectivity of the compound.

FIG. 2: The compound of the invention is non-immunogenic and does notinduce antibody formation after repeated injection into mice. AnimalsC1-C4 as well as animals C5-C8 were treated i.p. with two differentcompounds of the invention. Control animal C was vaccinated with aKLH-peptide derived from the human AChR protein MIR. UsingBSA-conjugated peptide probes T3-1, T9-1 and E005 (grey bars, asindicated in the graph), respectively, for antibody titer detection bystandard ELISA at a dilution of 1:100, it could be demonstrated thatantibody induction was absent in animals treated with a compound of theinvention, when compared to the vaccine-treated control animal C(y-axis, OD450 nm).

FIG. 3: Successful in vitro depletion of antibodies using SADCs carryingmultiple copies of monovalent or divalent peptides. SADCs with mono- ordivalent peptides were very suitable to adsorb antibodies and therebydeplete them. “Monovalent” means that peptide monomers are bound to thebiopolymer scaffold (i.e. n=1) whereas “divalent” means that peptidedimers are bound to the biopolymer scaffold (i.e. n=2). In the presentcase, the divalent peptides were “homodivalent”, i.e. the peptide n-merof the SADC is E006—spacer—E006).

FIG. 4: Rapid, selective antibody depletion in mice using various SADCbiopolymer scaffolds. Treated groups exhibited rapid and pronouncedantibody reduction already at 24 hrs (in particular SADC-TF) whencompared to the mock treated control group SADC-CTL (containing anunrelated peptide). SADC with albumin scaffold—SADC-ALB, SADC withimmunoglobulin scaffold—SADC-IG, SADC with haptoglobin scaffold-SADC-HP,and SADC with transferrin scaffold-SADC-TF.

FIG. 5: Detection of SADCs in plasma via their peptide moieties 24 hrsafter SADC injection. Both haptoglobin-scaffold-based SADCs (SADC-HP andSADC-CTL) exhibited a relatively shorter plasma half life whichrepresents an advantage over SADCs with other biopolymer scaffolds suchas SADC-ALB, SADC-IG oder SADC-TF. SADC with albumin scaffold-SADC-ALB,SADC with immunoglobulin scaffold-SADC-IG, SADC with haptoglobinscaffold-SADC-HP, and SADC with transferrin scaffold-SADC-TF.

FIG. 6: Detection of SADC-IgG complexes in plasma 24 hrs after SADCinjection. Haptoglobin based SADCs were subject to accelerated clearancewhen compared to SADCs with other biopolymer scaffolds. SADC withalbumin scaffold-SADC-ALB, SADC with immunoglobulin scaffold-SADC-IG,SADC with haptoglobin scaffold—SADC-HP, and SADC with transferrinscaffold—SADC-TF.

FIG. 7: In vitro analysis of SADC-IgG complex formation. Animals SADC-TFand -ALB showed pronounced immunocomplex formation and binding to Clq asreflected by the strong signals and by sharp signal lowering in case1000 ng/ml SADC-TF due to the transition from antigen-antibodyequilibrium to antigen excess. In contrast, in vitro immunocomplexformation with SADC-HP or SADC-IG were much less efficient when measuredin the present assay. These findings corroborate the finding thathaptoglobin scaffolds are advantageous over other SADC biopolymerscaffolds because of the reduced propensity to activate the complementsystem. SADC with albumin scaffold—SADC-ALB, SADC with immunoglobulinscaffold—SADC-IG, SADC with haptoglobin scaffold—SADC-HP, and SADC withtransferrin scaffold—SADC-TF.

FIG. 8: Determination of IgG capturing by SADCs in vitro. SADC-HP showedmarkedly less antibody binding capacity in vitro when compared toSADC-TF or SADC-ALB. SADC with albumin scaffold—SADC-ALB, SADC withimmunoglobulin scaffold—SADC-IG, SADC with haptoglobin scaffold—SADC-HP,and SADC with transferrin scaffold—SADC-TF.

EXAMPLES Example 1: The Compound of the Present Invention EffectivelyReduces the Titre of Undesired Antibodies

Animal models: In order to provide in vivo models with measurable titersof prototypic undesired antibodies in human indications, BALB/c micewere immunized using standard experimental vaccination withKLH-conjugated peptide vaccines derived from established humanautoantigens or anti-drug antibodies. After titer evaluation by standardpeptide ELISA, immunized animals were treated with the correspondingtest SADCs to demonstrate selective antibody lowering by SADC treatment.All experiments were performed in compliance with the guidelines by thecorresponding animal ethics authorities.

Immunization of mice with model antigens: Female BALB/c mice (aged 8-10weeks) were supplied by Janvier (France), maintained under a 12 hlight/12 h dark cycle and given free access to food and water.Immunizations were performed by s.c. application of KLHcarrier-conjugated peptide vaccines injected 3 times in biweeklyintervals. KLH conjugates were generated with peptide T3-2 (SEQ ID NO.14: CGRPQKRPSCIGCKG), which represents an example for molecular mimicrybetween a viral antigen (EBNA-1) and an endogenous human receptorantigen, namely the placental GPR50 protein, that was shown to berelevant to preeclampsia (Elliott et al.). In order to confirm thegenerality of this approach, a larger antigenic peptide derived from theautoimmune condition myasthenia gravis was used for immunization of micewith a human autoepitope. In analogy to peptide T3-2, animals wereimmunized with peptide T1-1 (SEQ ID NO. 15: LKWNPDDYGGVKKIHIPSEKGC),derived from the MIR (main immunogenic region) of the human AChR proteinwhich plays a fundamental role in pathogenesis of the disease (Luo etal.). The T1-1 peptide was used for immunizing mice with a surrogatepartial model epitope of the human AChR autoantigen. The peptide T8-1(SEQ ID NO. 16: DHTLYTPYHTHPG) was used to immunize control mice toprovide a control titer for proof of selectivity of the system. Forvaccine conjugate preparation, KLH carrier (Sigma) was activated withsulfo-GMBS (Cat. Nr. 22324 Thermo), according to the manufacturer'sinstructions, followed by addition of either N- or C-terminallycysteinylated peptides T3-2 and T1-1 and final addition of Alhydrogel®before injection into the flank of the animals. The doses for vaccinesT3-2 and T1-1 were 15 μg of conjugate in a volume of 100 ul perinjection containing Alhydrogel® (InvivoGen VAC-Alu-250) at a finalconcentration of 1% per dose.

Generation of prototypic SADCs: For testing selective antibody loweringactivity by SADCs of T3-2 and T1-1 immunized mice, SADCs were preparedwith mouse serum albumin (MSA) or mouse immunoglobulin (mouse-Ig) asbiopolymer scaffold in order to provide an autologous biopolymerscaffold, that will not induce any immune reaction in mice, ornon-autologuous human haptoglobin as biopolymer scaffold (that did notinduce an allogenic reaction after one-time injection within 72 hours).N-terminally cysteinylated SADC peptide E049 (SEQ ID NO. 13:GRPQKRPSCIG) and/or C-terminally cysteinylated SADC peptide E006 (SEQ IDNO. 4: VKKIHIPSEKG) were linked to the scaffold using sulfo-GMBS (Cat.Nr. 22324 Thermo)-activated MSA (Sigma; Cat. Nr. A3559) or -mouse-Ig(Sigma, 15381) or -human haptoglobin (Sigma H0138) according to theinstructions of the manufacturer, thereby providing MSA-, Ig- andhaptoglobin-based SADCs with the corresponding cysteinylated peptides,that were covalently attached to the lysines of the correspondingbiopolymer scaffold. Beside conjugation of the cysteinylated peptides tothe lysines via a bifunctional amine-to-sulfhydryl crosslinker, aportion of the added cysteinylated SADC peptides directly reacted withsulfhydryl groups of cysteins of the albumin scaffold protein, which canbe detected by treating the conjugates with DTT followed by subsequentdetection of free peptides using mass spectrometry or any otheranalytical method that detects free peptide. Finally, these SADCconjugates were dialysed against water using Pur-A-Lyzer™ (Sigma) andsubsequently lyophilized. The lyophilized material was resuspended inPBS before injection into animals.

In vivo functional testing of SADCs: Prototypic SADCs, SADC-E049 andSADC-E006 were injected intraperitoneally (i.p.; as a surrogate for anintended intravenous application in humans and larger animals) into themice that had previously been immunized with peptide vaccine T3-2(carrying the EBNA-1 model epitope) and peptide vaccine T1-1 (carryingthe AChR MIR model epitope). The applied dose was 30 μg SADC conjugatein a volume of 50 μl PBS. Blood takes were performed by submandibularvein puncture, before (−48 h, −24 h) and after (+24 h, +48 h, +72 h,etc.) i.p. SADC injections, respectively, using capillarymicro-hematocrit tubes. Using ELISA analysis (see below), it was foundthat both prototypic SADCs were able to clearly reduce the titers over aperiod of at least 72 hrs in the present animal model. It couldtherefore be concluded that SADCs can be used to effectively reducetiters in vivo.

Titer analysis: Peptide ELISAs were performed according to standardprocedures using 96-well plates (Nunc Medisorp plates; Thermofisher, CatNr 467320) coated for 1 h at RT with BSA-coupled peptides (30 nM,dissolved in PBS) and incubated with the appropriate buffers whileshaking (blocking buffer, 1% BSA, lx PBS; washing buffer, 1×PBS/0.1%Tween; dilution buffer, 1×PBS/0.1% BSA/0.1% Tween). After serumincubation (dilutions starting at 1:50 in PBS; typically in 1:3 or 1:2titration steps), bound antibodies were detected using HorseradishPeroxidase-conjugated goat anti-mouse IgG (Fc) from Jacksonimmunoresearch (115-035-008). After stopping the reaction, plates weremeasured at 450 nm for 20 min using TMB. EC50 were calculated fromreadout values using curve fitting with a 4-parameter logisticregression model (GraphPad Prism) according to the proceduresrecommended by the manufacturer. Constraining parameters for ceiling andfloor values were set accordingly, providing curve fitting qualitylevels of R²>0.98.

FIG. 1A shows an in vivo proof of concept in a mouse model for in vivoselective plasma-lowering activity of a prototypic albumin-based SADCcandidate that binds to antibodies directed against EBNA1, as a modelfor autoantibodies and mimicry in preeclampsia (Elliott et al.). Forthese mouse experiments, mouse albumin was used, in order to avoid anyreactivity against a protein from a foreign species. Antibody titerswere induced in 6 months old Balb/c mice by standard peptidevaccination. The bottom panel demonstrates that titers Log IC50 (y-axis)before SADC injection (i.e. titers at −48 h and −24 h) were higher thantiters Log IC50 after SADC application (i.e. titers+24 h, +48 h and +72h after injection; indicated on the x-axis).

A similar example is shown in FIG. 1B, using an alternative example of apeptidic antibody binding moiety for a different disease indication.Antibody lowering activity of an albumin-based SADC in a mouse modelthat was pre-immunized with a different peptide derived from the humanAChR protein MIR region (Luo et al.) in order to mimic the situation inmyasthenia gravis. The induced antibody titers against the AChR-MIRregion were used as surrogate for anti-AChR-MIR autoantibodies known toplay a causative role in myasthenia gravis (reviewed by Vincent et al.).A clear titer reduction was seen after SADC application.

FIGS. 1C and 1D demonstrate the functionality of SADC variantscomprising alternative biopolymer scaffolds. Specifically, FIG. 1C showsthat an immunoglobulin scaffold can be successfully used whereas FIG. 1Ddemonstrates the use of a haptoglobin-scaffold for constructing an SADC.Both examples show an in vivo proof of concept for selective antibodylowering by an SADC, carrying covalently bound example peptide E049.

The haptoglobin-based SADC was generated using human Haptoglobin as asurrogate although the autologuous scaffold protein would be preferred.In order to avoid formation of anti-human-haptoglobin antibodies, onlyone single SADC injection per mouse of the non-autologuous scaffoldhaptoglobin was used for the present experimental conditions. Asexpected, under the present experimental conditions (i.e. one-timeapplication), no antibody reactivity was observed against the presentsurrogate haptoglobin homologue.

FIG. 1E demonstrates the selectivity of the SADC system. Theimmunoglobulin-based SADC carrying the peptide E049 (i.e. the same as inFIG. 1C) cannot reduce the Ig-titer that was induced by a peptidevaccine with an unrelated, irrelevant aminoacid sequence, designatedpeptide T8-1 (SEQ ID NO. 16: DHTLYTPYHTHPG). The example shows an invivo proof of concept for the selectivity of the system. The top panelshows anti-peptide T8-1 titers (0.5× dilution steps starting from 1:50to 1:102400; X-axis shows log(X) dilutions) against OD values (y-axis)according to a standard ELISA. T8-1-titers are unaffected byadministration of SADC-Ig-E049 after application. The bottom paneldemonstrates that the initial titers Log IC50 (y-axis) before SADCinjection (i.e. titers at −48 h and −24 h) are unaffected byadministration of SADC-Ig-E049 (arrow) when compared to the titers LogIC50 after SADC application (i.e. titers+24 h, +48 h and +72 h; asindicated on the x-axis), thereby demonstrating the selectivity of thesystem.

Example 2: Immunogenicity of SADCs

In order to exclude immunogenicity of SADCs, prototypic candidate SADCswere tested for their propensity to induce antibodies upon repeatedinjection. Peptides T3-1 and T9-1 were used for this test. T3-1 is a10-amino acid peptide derived from a reference epitope of theAngiotensin receptor, against which agonistic autoantibodies are formedin a pre-eclampsia animal model (Zhou et al.); T9-1 is a 12-amino acidpeptide derived from a reference anti-drug antibody epitope of human IFNgamma (Lin et al.). These control SADC conjugates were injected 8× everytwo weeks i.p. into naïve, non-immunized female BALB/c mice starting atan age of 8-10 weeks.

Animals C1-C4 were treated i.p. (as described in example 1) with SADCT3-1. Animals C5-C8 were treated i.p. with an SADC carrying the peptideT9-1. As a reference signal for ELISA analysis, plasma from a controlanimal that was vaccinated 3 times with KLH-peptide T1-1 (derived fromthe AChR-MIR, explained in Example 1) was used. Using BSA-conjugatedpeptide probes T3-1, T9-1 and E005 (SEQ ID NO. 17: GGVKKIHIPSEK),respectively, for antibody titer detection by standard ELISA at adilution of 1:100, it could be demonstrated that antibody induction wasabsent in SADC-treated animals, when compared to the vaccine-treatedcontrol animal C (see FIG. 2). The plasmas were obtained bysubmandibular blood collection, 1 week after the 3rd vaccine injection(control animal C) and after the last of 8 consecutive SADC injectionsin 2-weeks intervals (animals C1-C8), respectively. Thus it wasdemonstrated that SADCs are non-immunogenic and do not induce antibodyformation after repeated injection into mice.

Example 3: Successful In Vitro Depletion of Antibodies Using SADCsCarrying Multiple Copies of Monovalent or Divalent Peptides

Plasma of E006-KLH (VKKIHIPSEKG (SEQ ID NO: 4) with C-terminal cysteine,conjugated to KLH) vaccinated mice was diluted 1:3200 in dilution buffer(PBS+0.1% w/v BSA+0.1% Tween20) and incubated (100 μl, room temperature)sequentially (10 min/well) four times on single wells of a microtiterplate that was coated with 2.5 μg/ml (250 ng/well) of SADC or 5 μg/ml(500 ng/well) albumin as negative control.

In order to determine the amount of free, unbound antibody presentbefore and after incubation on SADC coated wells, 50 μl of the dilutedserum were taken before and after the depletion and quantified bystandard ELISA using E006-BSA coated plates (10 nM peptide) anddetection by goat anti mouse IgG bio (Southern Biotech, diluted 1:2000).Subsequently, the biotinylated antibody was detected withStreptavidin-HRP (Thermo Scientific, diluted 1:5000) using TMB assubstrate. Development of the signal was stopped with 0.5 M sulfuricacid.

ELISA was measured at OD450 nm (y-axis). As a result, the antibody wasefficiently adsorbed by either coated mono- or divalent SADCs containingpeptide E006 with C-terminal cysteine (sequence VKKIHIPSEKGC, SEQ ID NO:4) (before=non-depleted starting material; mono-divalent corresponds topeptides displayed on the SADC surface; neg. control was albumin;indicated on the x-axis). See FIG. 3. (“Monovalent” means that peptidemonomers are bound to the biopolymer scaffold (i.e. n=1) whereas“divalent” means that peptide dimers are bound to the biopolymerscaffold (i.e. n=2). In the present case, the divalent peptides were“homodivalent”, i.e. the peptide n-mer of the SADC is E006-S-E006.)

This demonstrates that SADCs with mono- or divalent peptides are verysuitable to adsorb antibodies and thereby deplete them.

Example 4: Generation of Mimotope-Based SADCs

Linear and circular peptides derived from wild-type or modified peptideamino acid sequences can be used for the construction of specific SADCsfor the selective removal of harmful, disease-causing or otherwiseunwanted antibodies directed against a particular epitope. In case of aparticular epitope, linear peptides or constrained peptides such ascyclopeptides containing portions of an epitope or variants thereof,where for example, one or several amino acids have been substituted orchemically modified in order to improve affinity to an antibody(mimotopes), can be used for constructing SADCs. A peptide screen can beperformed with the aim of identifying peptides with optimized affinityto a disease-inducing autoantibody. The flexibility of structural orchemical peptide modification provided a solution to minimize the riskof immunogenicity, in particular of binding of the peptide to HLA andthus the risk of unwanted immune stimulation.

Therefore, wild-type as well as modified linear and circular peptidesequences were derived from a known epitope associated with anautoimmune disease. Peptides of various length and positions weresystematically permutated by amino acid substitutions and synthesized onthe PEPperCHIP® peptide array Platform (PEPperPRINT GmbH, Germany). Thisallowed screening of 60000 circular and linear wild-type and mimotopepeptides derived from these sequences. The peptide arrays were incubatedwith an autoantibody known to be involved in the autoimmune disease.This autoantibody was therefore used to screen the 60000 peptides and100 circular and 100 linear peptide hits were selected based on theirrelative binding strength to the autoantibody. Of these 200 peptides, 51sequences were identical between the circular and the linear peptidegroup. All of the best peptides identified had at least one amino acidsubstitution when aligned to the original sequences, respectively andare therefore regarded as mimotopes. It also turned out that higherbinding strengths can be achieved with circularized peptides.

These newly identified peptides, preferentially those with high relativebinding values, are used to generate SADCs that are able to removeautoantibodies directed against this particular epitope or to developfurther mimotopes and derivatives based on their sequences.

Example 5: Rapid, Selective Antibody Depletion in Mice Using VariousSADC Biopolymer Scaffolds

10 μg of model undesired antibody mAB anti V5 (Thermo Scientific) wasinjected i.p. into female Balb/c mice (5 animals per treatment group;aged 9-11 weeks) followed by intravenous injection of 50 μg SADC(different biopolymer scaffolds with tagged V5 peptides bound, seebelow) 48 hrs after the initial antibody administration. Blood wascollected at 24 hrs intervals from the submandibular vein. Blood samplesfor time point 0 hrs were taken just before SADC administration.

Blood was collected every 24 hrs until time point 120 hrs after the SADCadministration (x-axis). The decay and reduction of plasma anti-V5 IgGlevels after SADC administration was determined by anti V5 titer readoutusing standard ELISA procedures in combination with coatedV5-peptide-BSA (peptide sequence IPNPLLGLDC-SEQ ID NO: 21) and detectionby goat anti mouse IgG bio (Southern Biotech, diluted 1:2000) as shownin FIG. 4. In addition, SADC levels (see Example 6) and immunocomplexformation (see Example 7) were analyzed.

EC50[OD450] values were determined using 4 parameter logistic curvefitting and relative signal decay between the initial level (set to 1 attime point 0) and the following time points (x-axis) was calculated asratio of the EC50 values (y-axis, fold signal reduction EC50). All SADCpeptides contained tags for direct detection of SADC and immunocomplexesfrom plasma samples; peptide sequences used for SADCs were:IPNPLLGLDGGSGDYKDDDDKGK(SEQ ID NO: 22)-(BiotinAca)GC (SADC with albuminscaffold—SADC-ALB, SADC with immunoglobulin scaffold—SADC-IG, SADC withhaptoglobin scaffold—SADC-HP, and SADC with transferrinscaffold—SADC-TF) and unrelated peptide VKKIHIPSEKGGSGDYKDDDDKGK(SEQ IDNO: 23)-(BiotinAca)GC as negative control SADC (SADC-CTR).

The SADC scaffolds for the different treatment groups of 5 animals aredisplayed in black/grey shades (see inset of FIG. 4).

Treated groups exhibited rapid and pronounced antibody reduction alreadyat 24 hrs (in particular SADC-TF) when compared to the mock treatedcontrol group SADC-CTL. SADC-CTR was used as reference for a normalantibody decay since it has no antibody lowering activity because itspeptide sequence is not recognized by the administered anti V5 antibody.The decay of SADC-CTR is thus marked with a trend line, emphasizing theantibody level differences between treated and mock treated animals.

In order to determine the effectivity of selective antibody loweringunder these experimental conditions, a two-way ANOVA test was performedusing a Dunnett's multiple comparison test. 48 hrs after SADCadministration, the antibody EC50 was highly significantly reduced inall SADC groups (p<0.0001) compared to the SADC-CTR reference group(trend line). At 120 hrs after SADC administration, antibody decreasewas highly significant in the SADC-ALB and SADC-TF groups (bothp<0.0001) and significant in the SADC-HP group (p=0.0292), whereas theSADC-IG group showed a trend towards an EC50 reduction(p=0.0722) 120 hrsafter SADC administration. Of note, selective antibody reduction washighly significant (p<0.0001) in the SADC-ALB and SADC-TF groups at alltested time-points after SADC administration.

It is concluded that all SADC biopolymer scaffolds were able toselectively reduce antibody levels. Titer reduction was most pronouncedwith SADC-ALB and SADC-TF and no rebound or recycling of antibody levelswas detected towards the last time points suggesting that undesiredantibodies are degraded as intended.

Example 6: Detection of SADCs in Plasma 24 Hrs after SADC Injection

Plasma levels of different SADC variants at 24 hrs after i.v. injectioninto Balb/c mice. Determination of Plasma levels (y-axis) of SADC-ALB,-IG, -HP, -TF and the negative control SADC-CTR (x-axis), were detectedin the plasmas from the animals already described in example 5. Injectedplasma SADC levels were detected by standard ELISA whereby SADCs werecaptured via their biotin moieties of their peptides in combination withstreptavidin coated plates (Thermo Scientific). Captured SADCs weredetected by mouse anti Flag-HRP antibody (Thermo Scientific, 1:2,000diluted) detecting the Flag-tagged peptides (see also example 7):

Assuming a theoretical amount in the order of 25 μg/ml in blood afterinjecting 50 μg SADC i.v., the detectable amount of SADC ranged between799 and 623 ng/ml for SADC-ALB or SADC-IG and up to approximately 5000ng/ml for SADC-TF, 24 hrs after SADC injection. However surprisingly andin contrast, SADC-HP and control SADC-CTR (which is also a SADC-HPvariant, however carrying the in this case unrelated negative controlpeptide E006, see previous examples), had completely disappeared fromcirculation 24 hrs after injection, and were not detectable anymore. SeeFIG. 5.

This demonstrates that both Haptoglobin scaffold-based SADCs tested inthe present example ((namely SADC-HP and SADC-CTR) exhibit a relativelyshorter plasma half-life which represents an advantage over SADCs suchas SADC-ALB, SADC-IG oder SADC-TF in regard of their potential role incomplement-dependent vascular and renal damage due to the in vivo riskof immunocomplex formation. Another advantage of SADC-HP is theaccelerated clearance rate of their unwanted target antibody from bloodin cases where a rapid therapeutic effect is needed. The present resultsdemonstrate that Haptoglobin-based SADC scaffolds (as represented bySADC-HP and SADC-CTR) are subject to rapid clearance from the blood,regardless of whether SADC-binding antibodies are present in the blood,thereby minimizing undesirable immunocomplex formation and showing rapidand efficient clearance. Haptoglobin-based SADCs such as SADC-HP in thepresent example thus provide a therapeutically relevant advantage overother SADC biopolymer scaffolds, such as demonstrated by SADC-TF orSADC-ALB, both of which are still detectable 24 hrs after injectionunder the described conditions, in contrast to SADC-HP or SADC-CTR whichboth are completely cleared 24 hrs after injection.

Example 7: Detection of SADC-IgG Complexes in Plasma 24 Hrs after SADCInjection

In order to determine the amount IgG bound to SADCs in vivo, after i.v.injection of 10 μg anti V5 IgG (Thermo Scientific) followed by injectionof SADC-ALB, -HP, -TF and -CTR (50 μg) administered i.v. 48 h afterantibody injection, plasma was collected from the submandibular vein, 24hrs after SADC injection, and incubated on streptavidin plates forcapturing SADCs from plasma via their biotinylated SADC-V5-peptide[IPNPLLGLDGGSGDYKDDDDKGK(SEQ ID NO: 22) (BiotinAca)GC or in case ofSADC-CTR the negative control peptide VKKIHIPSEKGGSGDYKDDDDKGK(SEQ IDNO: 23) (BiotinAca)GC]. IgG bound to the streptavidin-captured SADCs wasdetected by ELISA using a goat anti mouse IgG HRP antibody (JacksonImmuno Research, diluted 1:2,000) for detection of the SADC-antibodycomplexes present in plasma 24 hrs after SADC injection. OD450 nm values(y-axis) obtained for a negative control serum from untreated animalswere subtracted from the OD450 nm values of the test groups (x-axis) forbackground correction.

As shown in FIG. 6, pronounced anti-V5 antibody signals were seen incase of SADC-ALB and SADC-TF injected mice (black bars representbackground corrected OD values at a dilution of 1:25, mean value of 5mice; standard deviation error bars), whereas no antibody signal couldbe detected in plasmas from SADC-HP or control SADC-CTR injected animals(SADC-CTR is a negative control carrying the irrelevant peptidebio-FLG-E006 [VKKIHIPSEKGGSGDYKDDDDKGK(SEQ ID NO: 23) (BiotinAca)GC]that is not recognized by any anti V5 antibody). This demonstrates theabsence of detectable amounts of SADC-HP/IgG complexes in the plasma 24hrs after i.v. SADC application.

SADC-HP is therefore subject to accelerated clearance in anti V5pre-injected mice when compared to SADC-ALB or SADC-TF.

Example 8: In Vitro Analysis of SADC-Immunoglobulin Complex Formation

SADC-antibody complex formation was analyzed by pre-incubating 1 μg/mlof human anti V5 antibody (anti V5 epitope tag [SVS—P-K], human IgG3,Absolute Antibody) with increasing concentrations of SADC-ALB, -IG, -HP,-TF and -CTR (displayed on the x-axis) in PBS+0.1% w/v BSA+0.1% v/vTween20 for 2 hours at room temperature in order to allow forimmunocomplex formation in vitro. After complex formation, samples wereincubated on ELISA plates that had previously been coated with 10 μg/mlof human Clq (CompTech) for 1 h at room temperature, in order to allowcapturing of in vitro formed immunocomplexes. Complexes weresubsequently detected by ELISA using anti human IgG (Fabspecific)-Peroxidase (Sigma, diluted 1:1,000). Measured signals at OD450nm (y-axis) reflect Antibody-SADC complex formation in vitro.

As shown in FIG. 7, SADC-TF and -ALB showed pronounced immunocomplexformation and binding to Clq as reflected by the strong signals and bysharp signal lowering in case 1000 ng/ml SADC-TF due to the transitionfrom antigen-antibody equilibrium to antigen excess. In contrast, invitro immunocomplex formation with SADC-HP or SADC-IG were much lessefficient when measured in the present assay.

Together with the in vivo data (previous examples), these findingscorroborate the finding that haptoglobin scaffolds are advantageous overother SADC biopolymer scaffolds because of the reduced propensity toactivate the complement system. In contrast, SADC-TF or SADC-ALB showhigher complexation, and thereby carry a certain risk of activating theC1 complex with initiation of the classical complement pathway (a riskwhich may be tolerable in some settings, however).

Example 9: Determination of IgG Capturing by SADCs In Vitro

Immunocomplexes were allowed to form in vitro, similar to the previousexample, using 1 μg/ml mouse anti V5 antibody (Thermo Scientific) incombination with increasing amounts of SADCs (displayed on the x-axis).SADC-antibody complexes were captured on a streptavidin coated ELISAplate via the biotinylated SADC-peptides (see previous examples),followed by detection of bound anti-V5 using anti mouse IgG-HRP (JacksonImmuno Research, diluted 1:2,000).

Under these assay conditions, SADC-HP showed markedly less antibodybinding capacity in vitro when compared to SADC-TF or SADC-ALB (see FIG.8, A). The calculated EC50 values for IgG detection on SADCs were 7.0ng/ml, 27.9 ng/ml and 55.5 ng/ml for SADC-TF, -ALB and -HP, respectively(see FIG. 8, B).

This in vitro finding is consistent with the observation (see previousexamples) that SADC-HP has a lower immunocomplex formation capacity whencompared to SADC-TF or SADC-ALB which is regarded as a safety advantagewith respect to its therapeutic use for the depletion of unwantedantibodies.

Example 10: SADCs to Reduce Undesired Antibodies Against AAV-8

Three SADCs are provided to reduce AAV-8-neutralizing antibodies whichhamper gene therapy (see Gurda et al. for the epitopes used; see alsoAAV-8 capsid protein sequence UniProt Q8JQF8, sequence version 1):

-   -   (a) SADC-a with haptoglobin as biopolymer scaffold and at least        two peptides with the sequence LQQQNT (SEQ ID NO: 18) covalently        bound to the scaffold,    -   (b) SADC-b with transferrin as biopolymer scaffold and at least        two peptides with the sequence TTTGQNNNS (SEQ ID NO: 19)        covalently bound to the scaffold, and    -   (c) SADC-c with albumin as biopolymer scaffold and at least two        peptides with the sequence GTANTQ (SEQ ID NO: 20) covalently        bound to the scaffold.

These SADCs are administered to an individual who will undergo genetherapy with AAV-8 as vector in order to increase efficiency of the genetherapy.

NON-PATENT REFERENCES

-   Carter, John Mark, and Larry Loomis-Price. “B cell epitope mapping    using synthetic peptides.” Current protocols in immunology 60.1    (2004): 9-4.-   Elliott, Serra E., et al. “A pre-eclampsia-associated Epstein-Barr    virus antibody cross-reacts with placental GPR50.” Clinical    Immunology 168 (2016): 64-71.-   Erlandsson, Ann, et al. “In vivo clearing of idiotypic antibodies    with antiidiotypic antibodies and their derivatives.” Molecular    immunology 43.6 (2006): 599-606.-   Garces, Jorge Carlos, et al. “Antibody-mediated rejection: a    review.” The Ochsner Journal 17.1 (2017): 46.-   Gazarian, Karlen, et al. “Mimotope peptides selected from phage    display combinatorial library by serum antibodies of pigs    experimentally infected with Taenia solium as leads to developing    diagnostic antigens for human neurocysticercosis.” Peptides 38.2    (2012): 381-388.-   Gfeller, David, et al. “Current tools for predicting cancer-specific    T cell immunity.” Oncoimmunology 5.7 (2016): e1177691.-   Gurda, Brittney L., et al. “Mapping a neutralizing epitope onto the    capsid of adeno-associated virus serotype 8.” Journal of virology    86.15 (2012): 7739-7751.-   Jansson, Liselotte, et al. “Immunotherapy With Apitopes Blocks the    Immune Response to TSH Receptor in HLA-DR Transgenic Mice.”    Endocrinology 159.9 (2018): 3446-3457.-   Jensen, Kamilla Kjaergaard, et al. “Improved methods for predicting    peptide binding affinity to MHC class II molecules.” Immunology    154.3 (2018): 394-406.-   Jurtz, Vanessa, et al. “NetMHCpan-4.0: improved peptide-MHC class I    interaction predictions integrating eluted ligand and peptide    binding affinity data.” The Journal of Immunology 199.9 (2017):    3360-3368.-   Koşaloğlu-Yalçin, et al. “Predicting T cell recognition of MHC class    I restricted neoepitopes.” Oncoimmunology 7.11 (2018): e1492508.-   Hansen, Lajla Bruntse, Soren Buus, and Claus Schafer-Nielsen.    “Identification and mapping of linear antibody epitopes in human    serum albumin using high-density peptide arrays.” PLoS One 8.7    (2013): e68902.-   Homma, Masayuki, et al. “A Novel Fusion Protein, AChR-Fc,    Ameliorates Myasthenia Gravis by Neutralizing Antiacetylcholine    Receptor Antibodies and Suppressing Acetylcholine Receptor-Reactive    B Cells.” Neurotherapeutics 14.1 (2017): 191-198.-   Howard Jr, James F. “Myasthenia gravis: the role of complement at    the neuromuscular junction.” Annals of the New York Academy of    Sciences 1412.1 (2018): 113-128.-   Howarth, M., & Brune, K. D. (2018). New routes and opportunities for    modular construction of particulate vaccines: stick, click and glue.    Frontiers in immunology, 9, 1432.-   Lazaridis, Konstantinos, et al. “Specific removal of autoantibodies    by extracorporeal immunoadsorption ameliorates experimental    autoimmune myasthenia gravis.” Journal of neuroimmunology 312    (2017): 24-30.-   Leung, Nicki Y H, et al. “Screening and identification of mimotopes    of the major shrimp allergen tropomyosin using one-bead-one-compound    peptide libraries.” Cellular & molecular immunology 14.3 (2017):    308-318.-   Lim, Sung In, and Inchan Kwon. “Bioconjugation of therapeutic    proteins and enzymes using the expanded set of genetically encoded    amino acids.” Critical reviews in biotechnology 36.5 (2016):    803-815.-   Lin, Chia-Hao, et al. “Identification of a major epitope by    anti-interferon-γ autoantibodies in patients with mycobacterial    disease.” Nature medicine 22.9 (2016): 994.-   Lorentz, Kristen M., et al. “Engineered binding to erythrocytes    induces immunological tolerance to E. coli asparaginase.” Science    advances 1.6 (2015): e1500112.-   Luo, Jie, et al. “Main immunogenic region structure promotes binding    of conformation-dependent myasthenia gravis autoantibodies,    nicotinic acetylcholine receptor conformation maturation, and    agonist sensitivity.” Journal of Neuroscience 29.44 (2009):    13898-13908.-   Luo, Jie, and Jon Lindstrom. “AChR-specific immunosuppressive    therapy of myasthenia gravis.” Biochemical pharmacology 97.4 (2015):    609-619.-   Majowicz, Anna, et al. “Seroprevalence of pre-existing NABs against    AAV1, 2, 5, 6 and 8 in the South African Hemophilia B patient    population.” (2019): 3353-3353.-   Mazor, Ronit, et al. “Tolerogenic nanoparticles restore the    antitumor activity of recombinant immunotoxins by mitigating    immunogenicity.” Proceedings of the National Academy of Sciences    115.4 (2018): E733-E742.-   Meister, Daniel, S. Maryamdokht Taimoory, and John F. Trant.    “Unnatural amino acids improve affinity and modulate immunogenicity:    Developing peptides to treat MHC type II autoimmune disorders.”    Peptide Science 111.1 (2019): e24058.-   Mingozzi, Federico, et al. “Overcoming preexisting humoral immunity    to AAV using capsid decoys.” Science translational medicine 5.194    (2013): 194ra92-194ra92.-   Mingozzi, Federico, and Katherine A. High. “Overcoming the host    immune response to adeno-associated virus gene delivery vectors: the    race between clearance, tolerance, neutralization, and escape.”    Annual review of virology 4 (2017): 511-534.-   Morimoto et. al., Bioconjugate Chemistry 25 (8) (2014): 1479-1491-   Moussa, Ehab M., et al. “Immunogenicity of therapeutic protein    aggregates.” Journal of pharmaceutical sciences 105.2 (2016):    417-430.-   Müller, Manuel M. “Post-translational modifications of protein    backbones: unique functions, mechanisms, and challenges.”    Biochemistry 57.2 (2017): 177-185.-   Siang Ong, Yong, et al. “Recent advances in synthesis and    identification of cyclic peptides for bioapplications.” Current    topics in medicinal chemistry 17.20 (2017): 2302-2318.-   Peters, Bjoern, et al. “A community resource benchmarking    predictions of peptide binding to MHC-I molecules.” PLoS    computational biology 2.6 (2006): e65.-   Pishesha, Novalia, et al. “Engineered erythrocytes covalently linked    to antigenic peptides can protect against autoimmune disease.”    Proceedings of the National Academy of Sciences (2017): 201701746.-   Rey et al., Clinical Immunology 96 (3) (2000): 269-279-   Ruff, Robert L., and Robert P. Lisak. “Nature and action of    antibodies in myasthenia gravis.” Neurologic clinics 36.2 (2018):    275-291.-   Rummler, Silke, et al. “Current techniques for AB0-incompatible    living donor liver transplantation.” World journal of    transplantation 6.3 (2016): 548.-   Runcie, Karie, et al. “Bi-specific and tri-specific antibodies—the    next big thing in solid tumor therapeutics.” Molecular Medicine 24.1    (2018): 50.-   Ryan, Brent J., Ahuva Nissim, and Paul G. Winyard. “Oxidative    post-translational modifications and their involvement in the    pathogenesis of autoimmune diseases.” Redox biology 2 (2014):    715-724.-   Shanmugam, Arulkumaran, et al. “Identification of PSA peptide    mimotopes using phage display peptide library.” Peptides 32.6    (2011): 1097-1102.-   Sorensen, Karen Kristine, et al. “Liver sinusoidal endothelial    cells.” Comprehensive Physiology 5.4 (2011): 1751-1774.-   Spiess, Christoph, Qianting Zhai, and Paul J. Carter. “Alternative    molecular formats and therapeutic applications for bispecific    antibodies.” Molecular immunology 67.2 (2015): 95-106.-   Taddeo, Adriano, et al. “Selection and depletion of plasma cells    based on the specificity of the secreted antibody.” European journal    of immunology 45.1 (2015): 317-319.-   Teschner, Sven, et al. “AB0-incompatible kidney transplantation    using regenerative selective immunoglobulin adsorption.” Journal of    clinical apheresis 27.2 (2012): 51-60.-   Tetala, Kishore K R, et al. “Selective depletion of    neuropathy-related antibodies from human serum by monolithic    affinity columns containing ganglioside mimics.” Journal of    medicinal chemistry 54.10 (2011): 3500-3505.-   Vincent, Angela, et al. “Serological and experimental studies in    different forms of myasthenia gravis.” Annals of the New York    Academy of Sciences 1413.1 (2018): 143-153.-   Wallukat, Gerd, et al. “Patients with preeclampsia develop agonistic    autoantibodies against the angiotensin AT 1 receptor.” The Journal    of clinical investigation 103.7 (1999): 945-952.-   Zhou, Cissy C., et al. “Angiotensin receptor agonistic    autoantibodies induce pre-eclampsia in pregnant mice.” Nature    medicine 14.8 (2008): 855.

What is claimed is:
 1. A compound comprising a biopolymer scaffold,wherein the biopolymer scaffold is a human protein, and at least a firstpeptide n-mer of the general formula:P(-S-P)_((n-1)) and a second peptide n-mer of the general formula:P(-S-P)_((n-1)); wherein, independently for each occurrence, P is apeptide with a sequence length of 2-13 amino acids and does not bind toany human leukocyte antigen (HLA) class I molecule, and S is anon-peptide spacer, wherein, independently for each of the peptiden-mers, n is an integer of at least 1, wherein each of the peptiden-mers is bound to the biopolymer scaffold.
 2. The compound of claim 1,wherein the biopolymer scaffold is selected from the group consisting ofhuman albumins, human alpha1-globulins, human alpha2-globulins and humanbeta-globulins.
 3. The compound of claim 2, wherein the biopolymerscaffold is a human transferrin.
 4. The compound of claim 2, wherein thebiopolymer scaffold is a human albumin.
 5. The compound of claim 1,wherein at least one occurrence of P is a circularized peptide.
 6. Thecompound of claim 1, wherein, independently for each occurrence, P isP_(a) or P_(b), wherein P_(a) is a peptide with a sequence length of2-13 amino acids, wherein P_(b) is a peptide with a sequence length of2-13 amino acids; and wherein the first peptide n-mer is P_(a)-S-P_(a)and the second peptide n-mer is P_(a)-S-P_(a), the first peptide n-meris P_(a)-S-P_(a) and the second peptide n-mer is P_(b)-S-P_(b), thefirst peptide n-mer is P_(b)-S-P_(b) and the second peptide n-mer isP_(b)-S-P_(b), the first peptide n-mer is P_(a)-S-P_(b) and the secondpeptide n-mer is P_(a)-S-P_(b), the first peptide n-mer is P_(a)-S-P_(b)and the second peptide n-mer is P_(a)-S-P_(a), or the first peptiden-mer is P_(a)-S-P_(b) and the second peptide n-mer is P_(b)-S-P_(b). 7.The compound of claim 6, wherein the peptide P_(a) and the peptide P_(b)are two different epitopes of the same antigen or two different epitopeparts of the same epitope.
 8. The compound of claim 1, wherein thecompound is non-immunogenic in a human.
 9. A pharmaceutical compositioncomprising the compound of claim 1 and at least one pharmaceuticallyacceptable excipient.
 10. The pharmaceutical composition of claim 9,wherein the composition is non-immunogenic in humans.
 11. A method ofsequestering one or more antibodies present in an individual, comprisingobtaining a pharmaceutical composition as defined in claim 9, whereinthe composition is non-immunogenic in the individual and wherein the oneor more antibodies present in the individual are specific for at leastone occurrence of P; and administering the pharmaceutical composition tothe individual.
 12. The method of claim 11, wherein the individual hasan autoimmune disease.
 13. The method of claim 12, wherein theautoimmune disease is selected from the group consisting ofneuromyelitis optica, seropositive neuromyelitis optica spectrumdisorders, autoimmune-encephalitis, multiple sclerosis, amyotrophiclateral sclerosis, systemic lupus erythematosus dementia, myastheniagravis, transient neonatal myasthenia gravis, dilatative Cardiomyopathy,pulmonary hypertension, Sjögren's Syndrome, celiac Disease, GravesDisease, Goodpasture Disease, preeclampsia, Behcet's Disease, systemicsclerosis, hypertension, type I diabetes, type II diabetes, systemiclupus erythematosus, anti N-methyl-D-aspartate receptor (NMDAR)encephalitis, antiphospholipid syndrome, membranous nephropathy, primarybiliary cholangitis, amyotrophic lateral sclerosis, Chagas diseasecardiomyopathy, immune thrombocytopenic purpura, pemphigus vulgaris,bullous pemphigoid, epidermolysis bullosa acquisita and bullous systemiclupus erythematosus.
 14. The method of claim 11, wherein the individualhas a transplant or has been selected for transplantation.
 15. Themethod of claim 11, wherein the individual is undergoing gene therapy orhas been selected for gene therapy.
 16. The method of claim 11, whereinthe individual is undergoing therapy with a drug or has been selectedfor therapy with the drug, wherein said one or more antibodies presentin the individual are also specific for the drug.
 17. The method ofclaim 16, wherein the drug is a peptide or a protein.
 18. The method ofclaim 17, wherein the drug is selected from the group of enzymes, enzymeinhibitors, antibodies, antibody fragments, antibody mimetics,antibody-drug conjugates, hormones, growth factors, clotting factors andcytokines.
 19. A pharmaceutical composition, comprising the compound ofclaim 1 and further comprising an active agent and at least onepharmaceutically acceptable excipient, wherein the active agentcomprises a peptide fragment with a sequence length of 2-13 amino acids,and wherein the sequence of at least one occurrence of peptide P of thecompound is at least 70% identical to the sequence of said peptidefragment.
 20. A method of inhibiting an immune reaction to a treatmentwith an active agent in an individual in need of treatment with theactive agent, comprising obtaining a pharmaceutical composition asdefined in claim 19; wherein the compound of the pharmaceuticalcomposition is non-immunogenic in the individual, and administering thepharmaceutical composition to the individual.